Compositions and methods to effect the release profile in the transdermal administration of active agents

ABSTRACT

Compositions and methods for the transdermal delivery of active agents up to a period of seven days or more at substantially a zero-order release rate comprising a pharmaceutically acceptable adhesive matrix and a polymeric plastic material that provides a release rate regulating effect on the active agents.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation application of U.S. Ser. No.09/765,932, filed Jan. 19, 2001 now abandoned, which is based on andclaims the benefit of Provisional Application No. 60/177,103, filed Jan.20, 2000. Both of these applications are incorporated in their entiretyherein by reference.

FIELD OF THE INVENTION

This invention relates generally to transdermal drug delivery systems,and more particularly to pharmaceutically acceptable adhesive matrixcompositions, that use polymeric plastic materials, in particularinsoluble cellulose derivatives such as ethyl celluloses, to regulatethe drug release profile. The invention additionally relates totransdermal drug delivery systems providing substantially zero orderdrug release profiles for an extended period of time of up to seven daysor longer.

BACKGROUND OF THE INVENTION

The use of transdermal drug delivery systems as a means to topicallyadminister an active agent is well known. Such systems incorporate theactive agent into a carrier composition, such as a polymeric and/orpressure-sensitive adhesive composition, from which the active agent isdelivered through the skin or mucosa of the user.

In general, transdermal drug delivery systems are either reservoir-typeor matrix-type devices. Both types of devices employ a backing layerthat forms the protective outer surface of the finished transdermalsystem and which is exposed to the environment during use, and a releaseliner or protective layer that forms the inner surface and which coverswhatever adhesive means is employed for affixing the system to the skinor mucosa of a user. The release liner or protective layer is removedprior to application, exposing the adhesive means, which is typically apressure-sensitive adhesive.

In the “classic” reservoir-type device, the active agent is usuallydissolved or dispersed in a carrier that typically yields a non-finitecarrier form, like a fluid or gel, and which is kept separate from theadhesive means used to affix the device to the user. The device has apocket or “reservoir” which physically serves to hold the active agentand carrier, and which is formed in or by the backing layer itself. Aperipheral adhesive layer is then used to affix the device to the user.The early reservoir-type devices incorporated drugs which were readilyabsorbed through the skin like nitroglycerin and nicotine.

Such devices have a number of disadvantages including a non-uniform drugrelease profile wherein a high dose of drug is released initially uponapplication to the user, often described as a “burst effect.” This burstor high initial release of drug then drops off after a period of time toa rate that is less than is able to achieve a therapeutically effectiveamount. Drug delivery according to this profile is described as firstorder release.

While such classic devices are still in use today, the term reservoir isbeing used interchangeably with matrix-type devices which still relyupon a separate adhesive means used to affix the device to the user.

In a matrix-type device, the active agent is dissolved or dispersed in acarrier that typically yields a finite carrier form, which can beself-adhesive or non-adhesive. Non-adhesive matrix-type devices, thatis, those which still rely upon a separate adhesive means to affix thedevice to the user, employ a drug permeable adhesive layer (oftenreferred to as an “in-line adhesive” since the drug must pass through),applied over the drug matrix carrier layer. In an attempt to bettercontrol the release rate of the drug, such devices often employ one ormore additional drug permeable layers such as rate controllingmembranes, or containing excipients, such as drug delivery enhancers.Hence, such devices are also commonly referred to as multilayer ormultilaminate.

In a “monolithic or monolayer” matrix-type device, the active agent istypically solubilized or homogenously blended in an adhesive carriercomposition, typically a pressure-sensitive adhesive or bioadhesive,which functions as both the drug carrier and the means of affixing thesystem to the skin or mucosa. Such devices, commonly referred to asdrug-in-adhesive devices, are described, for example, in U.S. Pat. Nos.4,994,267, 5,446,070, 5,474,783 and 5,656,286, all of which are assignedto Noven Pharmaceuticals, Inc., Miami, Fla.

While matrix-type devices, especially drug-in-adhesive devices, haveachieved more uniform and controlled drug deliver rates, and for longerperiods of time, most transdermal systems remain subject to a higherinitial drug release than is required to achieve therapeutic efficacy.For many drugs and/or therapeutic situations, it would be advantageousto eliminate or suppress this higher initial release and achieve a“steady state” (zero order) release profile which uniformly delivers atherapeutically effective amount of drug over the extended duration ofdevice's desired use.

For example, the high initial release of certain drugs may cause adverseor undesired effects, or create toxicity concerns, thereby foreclosingthe use of transdermal administration. In other instances, the higherinitial release may reduce the amount of drug required for treatment tothe point of risking underdosing, or may make it impractical to try andincrease the duration of the device's application while retainingtherapeutic effectiveness. The ability to reduce the frequency ofreplacing the transdermal drug delivery system would concomitantlyincrease user compliance, reduce any lag or drop off in efficacious.blood levels, and reduce the amount of drug required for treatment (alsoprovided by reducing the higher initial blood level associated with thehigher release rate).

Therefore, despite the existence of many different types of transdermaldelivery systems in the art, there remains a continuing need forimproving the release profile of drugs to achieve substantially zeroorder, as well as extending the duration of use of each transdermalsystem.

U.S. Pat. Ser. No. 07/897,269 discloses the use of glycerin tocounteract the burst effect of drugs in transdermal formulations.

It has now been found that the addition of certain polymeric plasticpolymers, in particular insoluble cellulose derivatives such as ethylcelluloses, into a pressure-sensitive adhesive matrix composition,eliminates or suppresses the initial high release rate of a drug subjectto a first order release rate profile such that the system achievessubstantially zero order release, and is able to maintain asubstantially zero order release profile for an extended period of timeup to seven days or longer.

Although not wishing to be bound by theory, particularly in this casewhere the structure of the composition has not been analyzed, it ispostulated that the insoluble polymeric plastic material affects theuptake/absorption of water or moisture from the application site intothe matrix composition which would otherwise create some of the kineticdriving force for release of the drug. This appears especiallysignificant in the presence of hydrophobic drugs and/or in conjunctionwith the use of hydrophilic crystallization inhibitors, such aspolyvinylpyrrolidones.

Ethyl celluloses have been extensively used in industrial applicationssince their commercial introduction in the mid-1930s. They arerecognized and widely used as well for many different purposes inpharmaceutical applications, especially in conjunction withwater-sensitive ingredients. Ethyl celluloses are most frequently usedas binders, fillers, flavor fixatives, controlled releasecoatings/barriers in microencapsulation and other solid dosage forms,particularly multiparticulate systems, granulation aids, tablet filmformers and taste maskers.

The prior art generally discloses the use of insoluble polymers such asethyl cellulose as optional components in transdermal systems asthickening agents and as cohesiveness strengthening agents which effectthe carrier's adhesive properties. For example, U.S. Pat. No. 5,232,702discloses the use of a variety of substances that include ethylcellulose and polyvinyl alcohol as cohesive strengthening agents(reducing flow properties of silicone adhesives) in a transdermaldelivery system.

The present invention is able to regulate the release profile of thedrug in a transdermal system without modifying the adhesive propertiesof the pressure-sensitive adhesive matrix so that the transdermal systempossesses the required degree of adhesion and tackiness to remainaffixed to the site of application for extended periods of time, whichcan be seven days or more, but at the same time can be easily removed asrequired.

The prior art further generally discloses the use of insoluble polymersin transdermal systems as the non-adhesive matrix carrier itself, andeven as a “suitable adhesive” for the matrix carrier itself (but whichpresumably includes the addition of a plasticizer or tackifier, orplasticizing liquid drug like nicotine, to create stickiness since suchpolymers are not adhesives). For example, U.S. Pat. No. 6,010,715discloses the use of thermoplastic polymers that are melt-blended withactive agents and enhancers that are heat stable at the melt temperatureof the polymer. The melt-blend can then be thermoformed into carrierlayers without the use of common solvents to produce a controlledrelease layer in a transdermal drug delivery system. Cellulosederivatives such as ethyl cellulose are generally disclosed as “suitableadhesives” for use as the matrix.

U.S. Pat. No. 5,904,931 discloses the use of ethyl cellulose as acrystallization inhibitor in a transdermal drug delivery system.Cellulose ether and polyvinyl compounds are generally described asadditional matrix additives.

SUMMARY OF THE INVENTION

It is therefore an objective of the present objective to provide formethods and pharmaceutically acceptable flexible, finite compositionsand systems for the transdermal administration of active agents thatachieve a substantially zero-order release profile when applied to auser.

It is another object of the invention to provide an adhesive matrix-typetransdermal drug delivery system which achieves a substantiallyzero-order release profile of the active agent by incorporating apolymeric plastic material into an adhesive drug matrix.

It is still another object of the invention to achieve a substantiallyzero-order release profile of the active agent for an extended period oftime of up to seven days or longer, and effectively continue to deliverthe active agent in a therapeutically effective amount.

It is a further object of the invention to provide a method ofeliminating or suppressing the high initial release or burst of activeagent from an adhesive matrix type transdermal drug delivery systemcontaining a drug subject to a first order release profile.

It is yet another object of the invention to provide a transdermal drugdelivery system that can deliver an active agent at substantiallyzero-order for an extended period of time in excess of 72 hours and upto seven days or more without substantially increasing the surface areaof the transdermal delivery system.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of a matrix-type transdermal drugdelivery system of the present invention.

FIG. 2 is a graphical representation comparing the in vitro flux rate ofestradiol and norethindrone acetate through cadaver skin from apressure-sensitive adhesive matrix composition of the present inventionwith the flux rate for a composition of the prior art.

FIG. 3 is a graphical representation of the in vitro first order fluxrate of estradiol through cadaver skin from a transdermal drug deliverysystem of the prior art as compared to the in vitro steady state fluxrate of estradiol through cadaver skin from an transdermal drug deliverysystem of the present invention.

FIG. 4 is a graphical representation of the in vitro flux rates ofestradiol through cadaver skin from two pressure-sensitive adhesivematrix compositions of the present invention using various amounts ofethyl cellulose as compared to the in vitro flux rate of estradiol froma pressure-sensitive adhesive matrix composition without ethylcellulose.

FIG. 5 is a graphical representation of the in vitro flux rates ofestradiol through cadaver skin from pressure-sensitive adhesive matrixcompositions of the present invention comparing the effect of varyingamounts of ethyl cellulose with varying amounts of estradiol.

FIG. 6 is a graphical representation of the in vitro flux rates ofestradiol and norethindrone acetate through cadaver skin frompressure-sensitive adhesive matrix compositions comparing the effect ofusing a combination of ethyl cellulose and cellulose acetate butyrateversus either polymer alone.

DETAILED DESCRIPTION OF THE INVENTION

The foregoing and other objects are achieved by this invention whichprovides a transdermal drug delivery system wherein the use of apolymeric plastic material provides a release rate regulating effect onthe active agents incorporated into the adhesive matrix composition.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention pertains.

The term “topical” or “topically” is used herein in its conventionalmeaning as referring to direct contact with an anatomical site orsurface area on a mammal including skin, teeth, nails and mucosa.

The term “mucosa” as used herein means any moist anatomical membrane orsurface on a mammal such as oral, buccal, vaginal, rectal, nasal orophthalmic surfaces.

The term “transdermal” as used herein means passage into and/or throughskin or mucosa for localized or systemic delivery of an active agent.

The term “solubilized” is intended to mean that in the carriercomposition there is an intimate dispersion or dissolution of the activeagent at the crystalline, molecular or ionic level. As such, the activeagent is considered herein to be in “non-crystallized” form when in thecompositions of the present invention.

As used herein, the term “flux” is defined as the absorption of the drugthrough the skin or mucosa, and is described by Fick's first law ofdiffusion:

J=−D(dCm/dx),

Where J is the flux in g/cm2/sec, D is the diffusion coefficient of thedrug through the skin or mucosa in cm2/sec and Dcm/dx is theconcentration gradient of the drug across the skin or mucosa.

The phrase “pharmaceutically acceptable flexible, finite” is intended tomean a solid form capable of conforming to a surface to which it isapplied, and which is capable of maintaining the contact in such solidform so as to facilitate topical application without adversephysiological response, and without being appreciably decomposed byaqueous contact during use by a subject.

The term “user” or “subject” is intended to include all warm-bloodedmammals, preferably humans.

The phrase “substantially zero-order” as used herein means transdermaldelivery of an active agent at a release rate which is approximatelyconstant once steady state is attained, typically within 12 to 24 hoursafter topical application. While variability in blood levels of activeagent are contemplated within the scope of this meaning once steadystate release is attained, the depletion rate of active agent over theduration of use should typically not exceed about 20% to about 25%.

Any polymeric plastic material may be employed for the present inventionprovided it is insoluble or substantially insoluble in water, andincludes cellulose derivatives such as cellulose acetates, (celluloseacetate butyrate, cellulose acetate propionate, cellulose acetatephthalate, etc.), methyl, ethyl and propyl celluloses; polycarbonates;polystyrenes; alkylacrylates such as polymethyl methacrylate, polyethylethacrylate, polyethylene methacrylate and other lower alkyl acrylates;vinyl polymers; polyurethanes; polyacrylonitriles; and mixtures,combinations and multipolymers (copolymers, terpolymers, etc.) thereof.

In preferred embodiments, the polymeric plastic material is a cellulosederivative. Preferred are cellulose esters such as cellulose acetatesincluding cellulose acetate, cellulose acetate butyrate, celluloseacetate phthalate, cellulose acetate propionate, and cellulose ethers.

Copending provisional application, Ser. No. 60/137,827, describes theuse of cellulose derivatives, particularly cellulose esters, as drugsolubility enhancers in matrix carrier compositions.

Particularly preferred cellulose ethers are ethyl cellulose polymers.Ethyl cellulose polymers can be manufactured in a variety of molecularweights, which translates into a range of viscosities when in solution.In practicing the subject invention, it has been found that solutionviscosities ranging from about 3 centipoise to about 49 centipoise arepreferred, and more preferably from about 6 centipoise to about 40centipoise, and optimally from about 6 centipoise to about 22 centipoise(viscosities are for 5% solutions, in 80% toluene and 20% ethanol,measured at 25° C. in an Ubbelohde viscometer). Ethyl cellulose polymershaving such solution viscosities exhibit melting point temperatures inthe range of about 165° C. to about 200° C. Suitable ethyl cellulosepolymers are commercially available and include those sold under thetrademark ETHOCEL® by the Dow Chemical Company, Midland, Mich. PreferredETHOCEL® polymers are ETHOCEL® Standard 7, 10, 14 and 20, Premium orIndustrial grades.

A crystallization inhibitor or solubility enhancer may also be employedin the invention, for example polyvinylpyrrolidone polymers,polyethylene oxide, polyacrylic acid, polyvinyl alcohol, siliconedioxide, silica, celluloses and cellulose derivatives such ashydroxymethyl cellulose, hydroxypropyl cellulose, gelatins, gums,starches, dextrins and dextrans, sterols, bile acids and otherabsorptive agents that possess the capability to absorb and hold wateror moisture.

Particularly preferred compounds are PVPs. The term“polyvinylpyrrolidone” or “PVP” refers to a polymer, ether a homopolymeror copolymer, containing vinylpyrrolidone (also referred to asN-vinylpyrrolidone, N-vinyl-2-pyrrolidone and N-vinyl-2-pyrrolidinone)as a monomeric unit. PVP polymers include soluble and insolublehomopolymeric PVPs, and copolymers such as vinylpyrrolidone/vinylacetate and vinylpyrrolidone/dimethylamino-ethylmethacrylate. Thecross-linked hompolymer (such as KOLLIDON® CL from BASF) is insolubleand is generally known in the pharmaceutical industry under thedesignations polyvinylpolypyrrolidone, crospovidone and PVP. Thecopolymer vinylpyrrolidone-vinyl acetate is generally known in thepharmaceutical industry under the designations Copolyvidon (e),Copolyvidonum or VP-VAc.

Particularly preferred PVPs are soluble. The term “soluble” when usedwith reference to PVP means that the polymer is soluble in water andgenerally is not substantially cross-linked, and has a molecular weightof less than about 2,000,000. See, generally, Buhler, KOLLIDON®:POLYVINYLPRYRROLIDONE FOR THE PHARMACEUTICAL INDUSTRY, BASFAktiengesellschaft (1992). Soluble PVP polymers have been identified inthe pharmaceutical industry under a variety of names, the most commonlyused include Povidone, Polyvidon (e), Polyvidonum, poly(N-vinyl-2-pyrrolidinone, poly (N-vinylbutyrolactam), poly(1-vinyl-2-pyrrolidinone, poly [1-(2-oxo-lpyrrolidinyl)ethylene].

The amount and type of PVP required in the preferred embodiments willdepend on the quantity and type of drug present in the adhesive matrixcomposition, as well as the type of adhesives, but can be readilydetermined through routine experimentation.

Typically, the PVP is present in an amount from about 5% to about 50% byweight, preferably from about 10% to about 40% by weight based on thedry weight of the total adhesive matrix composition. However, the amountof PVP can be higher than 20% for example, up to 40%, depending on theparticular drug used and on the desired properties of the matrix blend.

Said PVP preferably has a molecular weight of about 2,000 to 2,000,000,more preferably 5,000 to 100,000, and most preferably 7,000 to 54,000.PVP having a molecular weight of about 1,000,000 to about 1,500,000 isalso preferred.

PVPs are sold to the pharmaceutical industry under the trademarksKOLLIDON by BASF (Parsippanny, N.J.); PLASDONE, POLYPLASDONE andCOPOLYMER 958 by ISP Technologies, Wayne, N.J. Preferred PVPs areKOLLIDON 12PF, 17PF, 25, 30, 90 and VA-64.

Particularly preferred embodiments of the invention include soluble PVPin a polyacrylate and polysiloxane pressure-sensitive adhesive matrixblend.

The amount and type of polymeric plastic material required in thepractice of the invention will depend on the one or more additionalmaterials used in the adhesive matrix composition, and on the amount andtype of active agent(s). Generally, the amount of polymeric plasticmaterial to be used is an amount sufficient to deliver a therapeuticallyeffective amount of the active agent at a substantially zero-orderkinetic rate of delivery for an extended period of time of at leastthree days and up to seven days or longer, and to eliminate or suppressthe high initial release rate of a drug subject to a first order releaseprofile. Typically, the amount of polymeric plastic material to be usedranges from about 0.5% to about 30%, preferably from about 2.5% to 20%,and more preferably from about 5.0% to 15% by weight based on the dryweight of the total adhesive matrix composition. Amounts greater than30% typically result in loss of adhesive properties necessary tomaintain the system topically for an extended period of time.

The adhesive matrix compositions of the present invention are designedto effectively deliver an active agent in a therapeutically effectiveamount for an extended period of time up to seven days or longer. Asused herein, “therapeutically effective” means an amount of an activeagent that is sufficient to achieve the desired local or systemic effector result, such as to prevent, cure, diagnose, mitigate or treat adisease or condition, when applied topically over the duration ofintended use. Seven days is generally the preferred maximum duration forapplication of a transdermal drug delivery system of the presentinvention because the site of application is typically adverselyaffected when occluded for a period of time greater than seven days.However, if a non-occlusive backing material (i.e., permeable to watervapor and/or oxygen) is used, then the transdermal system may be appliedfor periods longer than seven days without adverse effects occurring, ifat all, until a much later time. While delivery of drug by the presentinvention is preferred for at least a seven-day continuous application,the transdermal system may be used discontinuously (i.e., replaced atany time during rather than at the end of the intended duration of use)since the drug release profile is substantially zero order.

The term “active agent” (and its equivalents “agent,” “drug,”“medicament” and “pharmaceutical”) is intended to have the broadestmeaning and includes at least one of any therapeutic, prophylactic,pharmacological or physiological active substance, cosmetic and personalcare preparations, and mixtures thereof, which is delivered to a mammalto produce a desired, usually beneficial, effect. More specifically, anyactive agent that is capable of producing a pharmacological response,localized or systemic, irrespective of whether therapeutic, diagnostic,cosmetic or prophylactic in nature, is within the contemplation of theinvention. It should be noted that the active agents can be usedsingularly or in combinations and mixtures.

There is no limitation on the type of active agent that can be used inthis invention. However, active agents that are solid or crystalline atroom temperature are preferred over liquid drugs, especially nicotine.Moreover, drug forms other than the free base form are also preferred.

The active agents contained in the adhesive matrix composition can be indifferent forms such as pharmaceutically acceptable salts, bases,esters, amides or pro-drugs, or may be modified by appending one or moreappropriate functionalities to enhance selected physical or biologicalproperties, for example as neutral molecules, components of molecularcomplexes or free bases to improve solubility or releasecharacteristics; or as pharmaceutically acceptable ethers, esters,amides and the like which have desirable retention and releasecharacteristics but which are easily metabolized at body pH.

Compounds may be converted into pharmaceutically acceptable salts, andthe salts may be converted into pharmaceutically acceptable freecompound using standard procedures known to those skilled in the art ofsynthetic organic chemistry and described, for example, by J. March,Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4^(th)Ed. (New York: Wiley-Interscience, 1992). Acid addition salts areprepared from the free base (e.g., compounds having a neutral —NH₂ orcyclic amine group) using conventional means, involving reaction with asuitable acid. An acid addition salt may be converted to the free baseby treatment with a suitable base. Basic salts of acid moieties whichmay be present (e.g., carboxylic acid groups) can be prepared in asimilar manner using pharmaceutically acceptable inorganic or organicbases. Compounds may also be converted into pharmaceutically acceptableesters. Suitable esters include branched or unbranched, saturated orunsaturated C₁ to C₆ alky esters, for example, methyl, ethyl and vinylesters. Preparation of esters involves functionalization of hydroxyland/or carboxyl groups which may be present. Pharmaceutically acceptableesters may be prepared using methods known to those skilled in the artand/or described in the pertinent literature. Esters can be reconvertedto the free acids, if desired, by using conventional hydrogenolysis orhydrolysis procedures. Preparation of amides and pro-drugs can beperformed in an analogous manner.

Steroids and hormonal active agents (including both natural,semi-synthetic and synthetic compounds and their derivatives havingsteroidal or hormonal activity) are preferred and include, for example,(a) estrogens such as Colpormon, Conjugated Estrogens, Estradiol (17β-and α-) and its Esters (e.g., Acetate, Benzoate, Cypionate, DipropionateDiacetate, Enanthate, Estradiol-16,17-Hemisuccinate, Undececenoate,Undecylate and Valerate), Estriol, Estrone, Ethinyl Estradiol,Equilenin, Equilin, Mestranol, Methyl Estradiol, Moxestrol,Mytatrienediol, Quinestradiol, Quinestrol, Dienestrol, Clomifen,Chlorotrianisen, and Cyclofenil; (b) progestagenically effectivehormones such as Allylestrenol, Anagestone, Chlormadinone Acetate,Delmadinone Acetate, Demegestone, Desogestrel, 3-Keto Desogestrel,Dimethisterone, Dydrogesterone, Ethinylestrenol, Ethisterone, Ethynodiol(and Diacetate), Flurogestone Acetate, Gestodene, Gestonorone Caproate,Haloprogesterone, (17-Hydroxy- and 17-Acetate-)16-Methylene-Progesterone, 17α-Hydroxyprogesterone (Acetate andCaproate), Levonorgestrel, Lynestrenol, Medrogestone,Medroxyprogesterone (and Acetate), Megestrol Acetate, Melengestrol,Norethindrone (Acetate and Enanthate), Norethisterone, Norethynodrel,Norgesterone, Norgestimate, Norgestrel, Norgestrienone,19-Norprogesterone, Norvinisterone, Pentagestrone, Progesterone,Promegestone, Quingestrone and Trengestone; and (c) androgenicallyeffective hormones such as Aldosterone, Androsterone, Boldenone,Cloxotestosterone, Dehydroepiandrosterone, Fluoxymesterone, Mestanolone,Mesterolone, Methandrostenolone, Methyltestosterone,17α-Methyltesteosterone, 17α-Methyltestosterone 3-Cyclopentyl EnolEther, Norethandrolone, Normethandrone, Oxandrolone, Oxymesterone,Oxymetholone, Prasterone, Stanlolone, Stanozolol, Testosterone (Acetate,Enanthate, Isobutyrate, Propionate and Undecanoate), Testosterone17-Chloral Hemiacetal, Testosterone 17β-Cypionate and Tiomesterone.

The adhesive matrix composition of the invention preferably contains17β-estradiol or ethinyl estradiol as the estrogen alone, or incombination with, Norethindrone (Acetate and Enanthate) orNorethisterone, as the progestagen, and mixtures thereof.

In embodiments containing combinations and mixtures of estrogens andprogestagens, the use of combinations and mixtures of cellulosederivatives, particularly cellulose esters and ethers, provide improveddrug release profiles for an extended period of time as compared to anadhesive matrix composition containing either one alone or none.Preferred combinations or mixtures of cellulose esters and ethers areethyl cellulose with cellulose acetate butyrate or with celluloseacetate propionate. When used in combinations and mixtures, the amountof each such polymer typically ranges from about 2.5% to about 10% byweight based on the dry weight of the total adhesive matrix composition.Particularly preferred embodiments of such mixtures and combinationsinclude soluble PVP, and typically in an amount of about 5% to about 15%by weight based on the dry weight of the total adhesive matrixcomposition.

As shown in FIG. 6, in pressure-sensitive adhesive matrix compositionscontaining both 17β-estradiol (E₂) and norethindrone acetate (NETA) in apolyacrylate/polysiloxane adhesive blend with 10% PVP, Formula 4comprising 5.0% ethyl cellulose and 5.0% cellulose acetate butyratedemonstrated an improved release profile as compared to either Formula 1(only 10% PVP), Formula 2 (5.0% ethyl cellulose) or Formula 3 (5.0%cellulose acetate butyrate). The foregoing formulas were prepared usingthe method of Example 1 to yield the following ingredient concentrationsset forth in tabular form in TABLE I.

TABLE I Formula 1 Formula 2 Formula 3 Formula 4 Polysiloxane 71.3 60.060.0 55.0 Adhesive (BIO-PSA ® 7-4603) Polyacrylate 0.0 5.0 5.0 5.0Adhesive (DURO-TAK ® 87-2287) Polyacrylate 5.0 0.0 0.0 0.0 Adhesive(Gelva ® 737) Ethyl Cellulose 0.0 5.0 0.0 5.0 (Ethocel ® 10) CelluloseAcetate 0.0 0.0 5.0 5.0 Butyrate (CAB-381-0.5) Polyvinylpyrrolidone 10.010.0 10.0 10.0 (KOLLIDON ® 30) Oleic Acid 6.0 0.0 0.0 0.0 DipropyleneGlycol 4.0 9.0 9.0 9.0 Oleyl Alcohol 0.0 6.0 6.0 6.0 Estradiol 0.7 1.01.0 1.0 Norethindrone 3.0 4.0 4.0 4.0 Acetate

Other specific drugs for which the invention can be particularlyusefully employed include:

1. α-Adrenergic agonists such as Adrafinil, Adrenolone, Amidephrine,Apraclonidine, Budralazine, Clonidine, Cyclopentamine, Detomidine,Dimetofrine, Dipivefrin, Ephedrine, Epinephrine, Fenoxazoline,Guanabenz, Guanfacine, Hydroxyamphetamine, Ibopamine, Indanazoline,Isometheptene, Mephentermine, Metaraminol, Methoxamine Hydrochloride,Methylhexaneamine, Metizolene, Midodrine, Naphazoline, Norepinephrine,Norfenefrine, Octodrine, Octopamine, Oxymetazoline, PhenylephrineHydrochloride, Phenylpropanolamine Hydrochloride,Phenylpropylmethylamine, Pholedrine, Propylhexedrine, Pseudoephedrine,Rilmenidine, Synephrine, Tetrahydrozoline, Tiamenidine, Tramazoline,Tuaminoheptane, Tymazoline, Tyramine and Xylometazoline.

2. β-Adrenergic agonists such as Albuterol, Bambuterol, Bitolterol,Carbuterol, Clenbuterol, Clorprenaline, Denopamine, Dioxethedrine,Dopexamine, Ephedrine, Epinephrine, Etafedrine, Ethylnorepinephrine,Fenoterol, Formoterol, Hexoprenaline, Ibopamine, Isoetharine,Isoproterenal, Mabuterol, Metaproterenol, Methoxyphenamine, Oxyfedrine,Pirbuterol, Prenalterol, Procaterol, Protokylol, Reproterol, Rimiterol,Ritodrine, Soterenol, Terbuterol and Xamoterol.

3. α-Adrenergic blockers such as Amosulalol, Arotinolol, Dapiprazole,Doxazosin, Ergoloid Mesylates, Fenspiride, Indoramin, Labetalol,Nicergoline, Prazosin, Terazosin, Tolazoline, Trimazosin and Yohimbine.

4. β-Adrenergic blockers such as Acebutolol, Alprenolol, Amosulalol,Arotinolol, Atenolol, Befunolol, Betaxolol, Bevantolol, Bisoprolol,Bopindolol, Bucumolol, Befetolol, Bufuralol, Bunitrolol, Bupranolol,Butidrine Hydrochloride, Butofilolol, Carazolol, Carteolol, Carvedilol,Celiprolol, Cetamolol, Cloranolol, Dilevalol, Epanolol, Esmolol,Indenolol, Labetalol, Levobunolol, Mepindolol, Metipranalol, Metoprolol,Moprolol, Nadoxolol, Nifenalol, Nipradilol, Oxprenolol, Penbutolol,Pindolol, Practolol, Pronethalol, Propranolol, Sotalol, Sulfinalol,Talinolol, Tertatolol, Timolol, Toliprolol and Xibenolol.

5. Alcohol deterrents such as Calcium Cyanamide Citrated, Disulfiram,Nadide and Nitrefazole.

6. Aldose reductase inhibitors such as Epalrestat, Ponalrestat, Sorbiniland Tolrestat.

7. Anabolics such as Androisoxazole, Androstenediol, Bolandiol,Bolasterone, Clostebol, Ethylestrenol. Formyldienolone,4-Hydroxy-19-nortestosterone, Methandriol, Methenolone,Methyltrienolone, Nandrolone, Nandrolone Decanoate, Nandrolonep-Hexyloxyphenylpropionate, Nandrolone Phenpropionate, Norbolethone,Oxymesterone, Pizotyline, Quinbolone, Stenbolone and Trenbolone.

8. Analgesics (dental) such as Chlorobutanol, Clove and Eugenol.

9. Analgesics (narcotic) such as Alfentanil, Allylprodine, Alphaprodine,Anileridine, Benzylmorphine, Bezitramide, Buprenorphine, Butorphanol,Clonitazene, Codeine, Codeine Methyl Bromide, Codeine Phosphate, CodeineSulfate, Desomorphine, Dextromoramide, Dezocine, Diampromide,Dihydrocodeine, Dihydrocodeinone Enol Acetate, Dihydromorphine,Dimenoxadol, Dimepheptanol, Dimethylthiambutene, Dioxaphetyl Butyrate,Dipipanone, Eptazocine, Ethoheptazine, Ethylmethlythiambutene,Ethylmorphine, Etonitazene, Fentanyl, Hydrocodone, HydrocodoneBitartrate, Hydromorphone, Hydroxypethidine, Isomethadone, Ketobemidone,Levorphanol, Lofentanil, Meperidine, Meptazinol, Metazocine, MethadoneHydrochloride, Metopon, Morphine, Morphine Derivatives, Myrophine,Nalbuphine, Narceine, Nicomorphine, Norlevorphanol, Normethadone,Normorphine, Norpipanone, Opium, Oxycodone, Oxymorphone, Papaveretum,Pentazocine, Phenadoxone, Phenazocine, Pheoperidine, Piminodine,Piritramide, Proheptazine, Promedol, Properidine, Propiram,Propoxyphene, Sufentanil and Tilidine.

10. Analgesics (non-narcotic) such as Acetaminophen, Acetaminosalol,Acetanilide, Acetylsalicylsalicylic Acid, Alclofenac, Alminoprofen,Aloxiprin, Aluminum Bis(acetylsalicylate), Aminochlorthenoxazin,2-Amino-4-picoline, Aminopropylon, Aminopyrine, Ammonium Salicylate,Antipyrine, Antipyrine Salicylate, Antrafenine, Apazone, Aspirin,Benorylate, Benoxaprofen, Benzpiperylon, Benzydamine,p-Bromoacetanilide, 5-Bromosalicylic Acid Acetate, Bucetin, Bufexamac,Bumadizon, Butacetin, Calcium Acetylsalicylate, Carbamazepine,Carbetidine, Carbiphene, Carsalam, Chloralantipyrine,Chlorthenoxazin(e), Choline Salicylate, Cinchophen, Ciramadol,Clometacin, Cropropamide, Crotethamide, Dexoxadrol, Difenamizole,Diflunisal, Dihydroxyaluminum Acetylsalicylate, Dipyrocetyl, Dipyrone,Emorfazone, Enfenamic Acid, Epirizole, Etersalate, Ethenzamide,Ethoxazene, Etodolac, Felbinac, Fenoprofen, Floctafenine, FlufenamicAcid, Fluoresone, Flupirtine, Fluproquazone, Flurbiprofen, Fosfosal,Gentisic Acid, Glafenine, Ibufenac, Imidazole Salicylate, Indomethacin,Indoprofen, Isofezolac, Isoladol, Isonixin, Ketoprofen, Ketorolac,p-Lactophenetide, Lefetamine, Loxoprofen, Lysine Acetylsalicylate,Magnesium Acetylsalicylate, Methotrimeprazine, Metofoline, Miroprofen,Morazone, Morpholine Salicylate, Naproxen, Nefopam, Nifenazone, 5′Nitro-2′ propoxyacetanilide, Parsalmide, Perisoxal, Phenacetin,Phenazopyridine Hydrochloride, Phenocoll, Phenopyrazone, PhenylAcetylsalicylate, Phenyl Salicylate, Phenyramidol, Pipebuzone,Piperylone, Prodilidine, Propacetamol, Propyphenazone, Proxazole,Quinine Salicylate, Ramifenazone, Rimazolium Metilsulfate, Salacetamide,Salicin, Salicylamide, Salicylamide O-Acetic Acid, Salicylsulfuric Acid,Salsalte, Salverine, Simetride, Sodium Salicylate, Sulfamipyrine,Suprofen, Talniflumate, Tenoxicam, Terofenamate, Tetradrine, Tinoridine,Tolfenamic Acid, Tolpronine, Tramadol, Viminol, Xenbucin and Zomepirac.

11. Anesthetics such as Acetamidoeugenol, Alfadolone Acetate,Alfaxalone, Amucaine, Amolanone, Amylocaine Hydrochloride, Benoxinate,Benzocaine, Betoxycaine, Biphenamine, Bupivacaine, Butacaine, Butaben,Butanilicaine, Burethamine, Buthalital Sodium, Butoxycaine, Carticaine,2-Chloroprocaine Hydrochloride, Cocaethylene, Cocaine, Cyclomethycaine,Dibucaine Hydrochloride, Dimethisoquin, Dimethocaine, DiperadonHydrochloride, Dyclonine, Ecgonidine, Ecgonine, Ethyl Aminobenzoate,Ethyl Chloride, Etidocaine, Etoxadrol, β-Eucaine, Euprocin, Fenalcomine,Fomocaine, Hexobarbital, Hexylcaine Hydrochloride, Hydroxydione Sodium,Hydroxyprocaine, Hydroxytetracaine, Isobutyl p-Aminobenzoate, Kentamine,Leucinocaine Mesylate, Levoxadrol, Lidocaine, Mepivacaine, MeprylcaineHydrochloride, Metabutoxycaine Hydrochloride, Methohexital Sodium,Methyl Chloride, Midazolam, Myrtecaine, Naepaine, Octacaine, Orthocaine,Oxethazaine, Parethoxycaine, Phenacaine Hydrochloride, Phencyclidine,Phenol, Piperocaine, Piridocaine, Polidocanol, Pramoxine, Prilocaine,Procaine, Propanidid, Propanocaine, Proparacaine, Propipocaine,Propofol, Propoxycaine Hydrochloride, Pseudococaine, Pyrrocaine, QuinineUrea Hydochloride, Risocaine, Salicyl Alcohol, Tetracaine Hydrochloride,Thialbarbital, Thimylal, Thiobutabarbital, Thiopental Sodium, Tolycaine,Trimecaine and Zolamine.

12. Anorexics such as Aminorex, Amphecloral, Amphetamine,Benzaphetamine, Chlorphentermine, Clobenzorex, Cloforex, Clortermine,Cyclexedrine, Destroamphetamine Sulfate, Diethylpropion,Diphemethoxidine, N-Ethylamphetamine, Fenbutrazate, Fenfluramine,Fenproporex, Furfurylmethylamphetamine, Levophacetoperate, Mazindol,Mefenorex, Metamfeproamone, Methamphetamine, Norpseudoephedrine,Phendimetrazine, Phendimetrazine Tartrate, Phenmetrazine,Phenpentermine, Phenylpropanolamine Hydrochloride and Picilorex.

13. Anthelmintics (Cestodes) such as Arecoline, Aspidin, Aspidinol,Dichlorophen(e), Embelin, Kosin, Napthalene, Niclosamide, Pellertierine,Pellertierine Tannate and Quinacrine.

14. Anthelmintics (Nematodes) such as Alantolactone, Amoscanate,Ascaridole, Bephenium, Bitoscanate, Carbon Tetrachloride, Carvacrol,Cyclobendazole, Diethylcarbamazine, Diphenane, Dithiazanine Iodide,Dymanthine, Gentian Violet, 4-Hexylresorcinol, Kainic Acid, Mebendazole,2-Napthol, Oxantel, Papain, Piperazine, Piperazine Adipate, PiperazineCitrate, Piperazine Edetate Calcium, Piperazine Tartrate, Pyrantel,Pyrvinium Pamoate, á-Santonin, Stilbazium Iodide, Tetrachloroethylene,Tetramisole, thiabendazole, Thymol, Thymyl N-Isoamylcarbamate,Triclofenol Piperazine and Urea Stibamine.

15. Anthelmintics (Onchocerca) such as Ivermectin and Suramin Sodium.

16. Anthelmintics (Schistosoma) such as Amoscanate, Amphotalide,Antimony Potassium Tartrate, Antimony Sodium Gluconate, Antimony SodiumTartrate, Antimony Sodium Thioglycollate, Antimony Thioglycollamide,Becanthone, Hycanthone, Lucanthone Hydrochloride, Niridazole,Oxamniquine, Praziquantel, Stibocaptate, Stibophen and Urea Stibamine.

17. Anthelmintic (Trematodes) such as Anthiolimine andTetrachloroethylene.

18. Antiacne drugs such as Adapelene, Algestone Acetophenide, AzelaicAcid, Benzoyl Peroxide, Cyoctol, Cyproterone, Motretinide, Resorcinol,Retinoic Acid, Tetroquinone and Tretinonine.

19. Antiallergics such as Amlexanox, Astemizole, Azelastine, Cromolyn,Fenpiprane, Histamine, Ibudilast, Nedocromil, Oxatomide, Pentigetide,Poison Ivy Extract, Poison Oak Extract, Poison Sumac Extract,Repirinast, Tranilast, Traxanox and Urushiol.

20. Antiamebics such as Arsthinol, Bialamicol, Carbarsone, Cephaeline,Chlorbetamide, Chloroquine, Chlorphenoxamide, Chlortetracycline,Dehydroemetine, Dibromopropamidine, Diloxanide, Dephetarsone, Emetine,Fumagillin, Glaucarubin, Glycobiarsol,8-Hydroxy-7-iodo-5-quinolinesulfonic Acid, Iodochlorhydroxyquin,Iodoquinol, Paromomycin, Phanquinone, Phearsone Sulfoxylate,Polybenzarsol, Propamidine, Quinfamide, Secnidazole, Sulfarside,Teclozan, Tetracycline, Thiocarbamizine, Thiocarbarsone and Tinidazole.

21. Antiandrogens such as Bifluranol, Cyoctol, Cyproterone, DelmadinoneAcetate, Flutimide, Nilutamide and Oxendolone.

22. Antianginals such as Acebutolol, Alprenolol, Amiodarone, Amlodipine,Arotinolol, Atenolol, Bepridil, Bevantolol, Bucumolol, Bufetolol,Bufuralol, Bunitrolol, Bupranolol, Carozolol, Carteolol, Carvedilol,Celiprolol, Cinepazet Maleate, Diltiazem, Epanolol, Felodipine,Gallopamil, Imolamine, Indenolol, Isosorbide Dinitrate, Isradipine,Limaprost, Mepindolol, Metoprolol, Molsidomine, Nadolol, Nicardipine,Nifedipine, Nifenalol, Nilvadipine, Nipradilol, Nisoldipine,Nitroglycerin, Oxprenolol, Oxyfedrine, Ozagrel, Penbutolol,Pentaerythritol Tetranitrate, Pindolol, Pronethalol, Propranolol,Sotalol, Terodiline, Timolol, Toliprolol and Verapamil.

23. Antiarrhythmics such as Acebutol, Acecaine, Adenosine, Ajmaline,Alprenolol, Amiodarone, Amoproxan, Aprindine, Arotinolol, Atenolol,Bevantolol, Bretylium Tosylate, Bubumolol, Bufetolol, Bunaftine,Bunitrolol, Bupranolol, Butidrine Hydrochloride, Butobendine, CapobenicAcid, Carazolol, Carteolol, Cifenline, Cloranolol, Disopyramide,Encainide, Esmolol, Flecainide, Gallopamil, Hydroquinidine, Indecainide,Indenolol, Ipratropium Bromide, Lidocaine, Lorajmine, Lorcainide,Meobentine, Metipranolol, Mexiletine, Moricizine, Nadoxolol, Nifenalol,Oxprenolol, Penbutolol, Pindolol, Pirmenol, Practolol, Prajmaline,Procainamide Hydrochloride, Pronethalol, Propafenone, Propranolol,Pyrinoline, Quinidine Sulfate, Quinidine, Sotalol, Talinolol, Timolol,Tocainide, Verapamil, Viquidil and Xibenolol.

24. Antiarteriosclerotics such as Pyridinol Carbamate.

25. Antiarthritic/Antirheumatics such as Allocupreide Sodium, Auranofin,Aurothioglucose, Aurothioglycanide, Azathioprine, Calcium3-Aurothio-2-propanol-1-sulfonate, Celecoxib, Chloroquine, Clobuzarit,Cuproxoline, Diacerein, Glucosamine, Gold Sodium Thiomalate, Gold SodiumThiosulfate, Hydroxychloroquine, Kebuzone, Lobenzarit, Melittin,Methotrexate, Myoral and Penicillamine.

26. Antibacterial (antibiotic) drugs including:

Aminoglycosides such as Amikacin, Apramycin, Arbekacin, Bambermycins,Butirosin, Dibekacin, Dihdrostreptomycin, Fortimicin(s), Gentamicin,Ispamicin, Kanamycin, Micronomicin, Neomycin, Neomycin Undecylenate,Netilmicin, Paromomycin, Ribostamycin, Sisomicin, Spectinomycin,Streptomycin, Streptonicozid and Tobramycin;

Amphenicols such as Azidamfenicol, Chloramphenicol, ChloramphenicolPalmitate, Chloramphenicol Pantothenate, Florfenicol and Thiamphenicol;

Ansamycins such as Rifamide, Rifampin, Rifamycin and Rifaximin;

β-Lactams, including:

Carbapenems such as Imipenem;

Cephalosporins such as Cefactor, Cefadroxil, Cefamandole, Cefatrizine,Cefazedone, Cefazolin, Cefixime, Cefmenoxime, Cefodizime, Cefonicid,Cefoperazone, Ceforanide, Cefotaxime, Cefotiam, Cefpimizole,Cefpirimide, Cefpodoxime Proxetil, Cefroxadine, Cefsulodin, Ceftazidime,Cefteram, Ceftezole, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime,Cefuzonam, Cephacetrile Sodium, Cephalexin, Cephaloglycin,Cephaloridine, Cephalosporin, Cephalothin, Cephapirin Sodium, Cephradineand Pivcefalexin;

Cephamycins such as Cefbuperazone, Cefmetazole, Cefminox, Cefetan andCefoxitin;

Monobactams such as Aztreonam, Carumonam and Tigemonam;

Oxacephems such as Flomoxef and Moxolactam;

Penicillins such as Amidinocillin, Amdinocillin Pivoxil, Amoxicillin,Ampicillan, Apalcillin, Aspoxicillin, Azidocillan, Azlocillan,Bacampicillin, Benzylpenicillinic Acid, Benzylpenicillin Sodium,Carbenicillin, Carfecillin Sodium, Carindacillin, Clometocillin,Cloxacillin, Cyclacillin, Dicloxacillin, Diphenicillin Sodium,Epicillin, Fenbenicillin, Floxicillin, Hetacillin, Lenampicillin,Metampicillin, Methicillin Sodium, Mezlocillin, Nafcillin Sodium,Oxacillin, Penamecillin, Penethamate Hydriodide, Penicillin GBenethamine, Penicillin G Benzathine, Penicillin G Benzhydrylamine,Penicillin G Calcium, Penicillin G Hydrabamine, Penicillin G Potassium,Penicillin G Procaine, Penicillen N, Penicillin O, Penicillin V,Penicillin V Benzathine, Penicillin V Hydrabamine, Penimepicycline,Phenethicillin Potassium, Piperacillin, Pivapicillin, Propicillin,Quinacillin, Sulbenicillin, Talampicillin, Temocillin and Ticarcillin;

Lincosamides such as Clindamycin and Lincomycin;

Macrolides such as Azithromycin, Carbomycin, Clarithromycin,Erythromycin, Erythromycin Acistrate, Erythromycin Estolate,Erythromycin Glucoheptonate, Erythromycin Lactobionate, ErythromycinPropionate, Erythromycin Stearate, Josamycin, Leucomycins, Midecamycins,Miokamycin, Oleandomycin, Primycin, Rokitamycin, Rosaramicin,Roxithromycin, Spiramycin and Troleandomycin;

Polypeptides such as Amphomycin, Bacitracin, Capreomycin, Colistin,Enduracidin, Enviomycin, Fusafungine, Gramicidin(s), Gramicidin S,Mikamycin, Polymyxin, Polymyxin B-Methanesulfonic Acid, Pristinamycin,Ristocetin, Teicoplanin, Thiostrepton, Tuberactinomycin, Tyrocidine,Tyrothricin, Vancomycin, Viomycin, Viomycin Pantothenate, Virginiamycinand Zinc Bacitracin;

Tetracyclines such as Apicycline, Chlortetracycline, Clomocycline,Demeclocycline, Doxycycline, Guamecycline, Lymecycline, Meclocycline,Methacycline, Minocycline, Oxytetracycline, Penimepicycline,Pipacycline, Rolitetracycline, Sancycline, Senociclin and Tetracycline;and

other antibiotics such as Cycloserine, Mupirocin and Tuberin.

27. Antibacterial drugs (synthetic), including:

2,4-Diaminopyrimidines such as Brodimoprim, Tetroxoprim andTrimethoprim;

Nitrofurans such as Furaltadone, Furazolium Chloride, Nifuradene,Nifuratel, Nifurfoline, Nifurpirinol, Nifurprazine, Nifurtoinol andNitrofurantoin;

Quinolones and Analogs such as Amifloxacin, Cinoxacin, Ciprofloxacin,Difloxacin, Enoxacin, Fleroxacin, Flumequine, Lomefloxacin, Miloxacin,Nalidixic Acid, Norfloxacin, Ofloxacin, Oxolinic Acid, Pefloxacin,Pipemidic Acid, Piromidic Acid, Rosoxacin, Temafloxacin andTosufloxacin;

Sulfonamides such as Acetyl Sulfamethoxypyrazine, Acetyl Sulfisoxazole,Azosulfamide, Benzylsulfamide, Chloramine-B, Chloramine-T, DichloramineT, Formosulfathiazole, N²Formylsulfisomidine,N²-â-D-Glucosylsulfanilamide, Mafenide,4′-(Methylsulfamoyl)sulfanilanilide, p-Nitrosulfathiazole,Noprylsulfamide, Phthalylsulfacetamide, Phthalylsulfathiazole,Salazosulfadimidine, Succinylsulfathiazole, Sulfabenzamide,Sulfacetamide, Sulfachlorpyridazine, Sulfachrysoidine, Sulfacytine,Sulfadiazine, Sulfadicramide, Sulfadimethoxine, Sulfadoxine,Sulfaethidole, Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfaloxic Acid,Sulfamerazine, Sulfameter, Sulfamethazine, Sulfamethizole,Sulfamethomidine, Sulfamethoxazole, Sulfamethoxypyridazine,Sulfametrole, Sulfamidochrysoidine. Sulfamoxole, Sulfanilamide,Sulfanilamidomethanesulfonic Acid Triethanolamine Salt,4-Sulfanilamidosalicylic Acid, N⁴-Sulfanilylsulfanilamide,Sulfanilylurea, N-Sulfanilyl-3, 4-xylamide, Sulfanitran, Sulfaperine,Sulfaphenazole. Sulfaproxyline, Sulfapyrazine, Sulfapyridine,Sulfasomizole, Sulfasymazine, Sulfathiazole, Sulfathiourea,Sulfatolamide, Sulfisomidine and Sulfisoxazole;

Sulfones such as Acedapsone, Acediasulfone, Acetosulfone Sodium,Dapsone, Diathymosulfone, Glucosulfone Sodium, Solasulfone,Succisulfone, Sulfanilic Acid, p-Sulfanilylbenzylamine,p,p′-Sulfonyldianiline-N.N′ digalactoside, Sulfoxone Sodium andThiazolsulfone; and others such as Clofoctol, Hexedine, Methenamine,Methenamine Anhydromethylene-citrate, Methenamine Hippurate, MethenamineMandelate, Methenamine Sulfosalicylate, Nitroxoline and Xibornol.Anticholinergics such as Adiphenine Hydrochloride, Alverine,Ambutonomium Bromide, Aminopentamide, Amixetrine, AmprotropinePhosphate, Anisotropine Methylbromide, Apoatropine, Atropine, AtropineN-Oxide, Benactyzine, Benapryzine, Benzetimide, Benzilonium Bromide,Benztropine Mesylate, Bevonium Methyl Sulfate, Biperiden, ButropiumBromide, N-Butylscopolammonium Bromide, Buzepide, Camylofine, CaramiphenHydrochloride, Chlorbenzoxamine, Chlorphenoxamine, Cimetropium Bromide,Clidinium Bromide, Cyclodrine, Cyclonium Iodide, CycrimineHydrochloride, Deptropine, Dexetimide, Dibutoline Sulfate, DicyclomineHydrochloride, Diethazine, Difemerine, Dihexyverine, DiphemanilMethylsulfate, N-(1,2-Diphenylethyl)nicotinamide, Dipiproverine,Diponium Bromide, Emepronium Bromide, Endobenzyline Bromide,Ethopropazine, Ethybenztropine, Ethylbenzhydramine, Etomidoline,Eucatropine, Fenpiverinium Bromide, Fentonium Bromide, FlutropiumBromide, Glycopyrrolate, Heteronium Bromide, Hexocyclium Methyl Sulfate,Homatropine, Hyoscyamine, Ipratropium Bromide, Isopropamide, Levomepate,Mecloxamine, Mepenzolate Bromide, Metcaraphen, Methantheline Bromide,Methixene, Methscopolamine Bromide, Octamylamine, Chloride,Oxyphencyclimine, Oxyphenonium Bromide, Pentapiperide, PenthienateBromide, Phencarbamide, Phenglutarimide, Pipenzolate Bromide,Piperidolate, Piperilate, Poldine Methysulfate, Pridinol, PrifiniumBromide, Procyclidine, Propantheline Bromide, Propenzolate,Propyromazine, Scopolamine, Scopolamine N-Oxide, Stilonium Iodide,Stramonium, Sultroponium, Thihexinol, Thiphenamil, Tiemonium Iodide,Timepidium Bromide, Tiquizium Bromide, Tridihexethyl Iodide,Trihexyphenidyl Hydrochloride, Tropacine, Tropenzile, Tropicamide,Trospium Chloride, Valethamate Bromide and Xenytropium Bromide.

28. Anticonvulsants such as Acetylpheneturide, Albutoin, Aloxidone,Aminoglutethimide, 4-Amino-3-hydroxybutyric Acid, Atrolactamide,Beclamide, Buramate, Calcium Bromide, Carbamazepine, Cinromide,Clomethiazole, Clonazepam, Decimemide, Diethadione, Dimethadione,Doxenitoin, Eterobarb, Ethadione, Ethosuximide, Ethotoin, Fluoresone,Garbapentin, 5-Hydroxytryptophan, Lamotrigine, Lomactil, MagnesiumBromide, Magnesium Sulfate, Mephenytoin, Mephobarbital, Metharbital,Methetoin, Methsuximide, 5-Methyl-5-(3-phenanthryl)hydantoin,3-Methyl-5-phenylhydantoin, Narcobarbital, Nimetazepam, Nitrazepam,Paramethadione, Phenacemide, Phenetharbital, Pheneturide, Phenobarbital,Phenobarbital Sodium, Phensuximide, Phenylmethylbarbituric Acid,Phenytoin, Phethenylate Sodium, Potassium Bromide, Pregabatin,Primidone, Progabide, Sodium Bromide, Sodium Valproate, Solanum,Strontium Bromide, Suclofenide, Sulthiame, Tetrantoin, Tiagabine,Trimethadione, Valproic Acid, Valpromide, Vigabatrin and Zonisamide.

29. Antidepressants, including:

Bicyclics such as Binedaline, Caroxazone, Citalopram, Dimethazan,Indalpine, Fencamine, Indeloxazine Hydrochcloride, Nefopam, Nomifensine,Oxitriptan, Oxypertine, Paroxetine, Sertraline, Thiazesim, Trazodone,Venlafaxine and Zometapine;

Hydrazides/Hydrazines such as Benmoxine, Iproclozide, Iproniazid,Isocarboxazid, Nialamide, Octamoxin and Phenelzine;

Pyrrolidones such as Cotinine, Rolicyprine and Rolipram;

Tetracyclics such as Maprotiline, Metralindole, Mianserin andOxaprotiline.

Tricyclics such as Adinazolam, Amitriptyline, Amitriptylinoxide,Amoxapine, Butriptyline, Clomipramine, Demexiptiline, Desipramine,Dibenzepin, Dimetracrine, Dothiepin, Doxepin, Fluacizine, Imipramine,Imipramine N-Oxide, Iprindole, Lofepramine, Melitracen, Metapramine,Nortriptyline, Noxiptilin, Opipramol, Pizotyline, Propizepine,Protriptyline, Quinupramine, Tianeptine and Trimipramine; and

others such as Adrafinil, Benactyzine, Bupropion, Butacetin, Deanol,Deanol Aceglumate, Deanol Acetamidobenzoate, Dioxadrol, Etoperidone,Febarbamate, Femoxetine, Fenpentadiol, Fluoxetine, Fluvoxamine,Fluvoxamine Maleate, Hematoporphyrin, Hypercinin, Levophacetoperane,Medifoxamine, Minaprine, Moclobemide, Oxaflozane, Piberaline,Prolintane, Pyrisuccideanol, Rubidium Chloride, Sulpiride, Sultopride,Teniloxazine, Thozalinone, Tofenacin, Toloxatone, Tranylcypromine,L-Tryptophan, Viloxazine and Zimeldine.

30. Antidiabetics, including:

Biguanides such as Buformin, Metformin and Phenformin;

Hormones such as Glucagon and Insulin;

Sulfonylurea derivatives such as Acetohexamide, 1-Butyl-3-metanilylurea,Carbutamide, Chlorpropamide, Glibornuride, Gliclazide, Glipizide,Gliquidone, Glisoxepid, Glyburide, Glybuthiazol(e), Glybuzole,Glyhexamide, Glymidine, Glypinamide, Phenbutamide, Tolazamide,Tolbutamide and Tolcyclamide; and

others such as Acarbose, Calcium Mesoxalate and Miglitol.

31. Antidiarrheal drugs such as Acetyltannic Acid, Albumin Tannate,Alkofanone, Aluminum Salicylates—Basic, Catechin, Difenoxin,Diphenoxylate, Lidamidine, Lomotil, Loperamide, Mebiquine, Trillium andUzarin.

32. Antidiuretics such as Desmopressin, Felypressin, Lypressin,Ornipressin, Oxycinchophen, Pituitary—Posterior, Terlipressin andVasopressin.

33. Antiestrogens such as Delmadinone Acetate, Ethamoxytriphetol,Tamoxifen and Toremifene.

34. Antifungal drugs (antibiotics), including:

Polyenes such as Amphotericin-B, Candicidin, Dermostatin, Filipin,Fungichromin, Hachimycin, Hamycin, Lucensomycin, Mepartricin, Natamycin,Nystatin, Pecilocin and Perimycin; and

others such as Azaserine, Griseofulvin, Oligomycins, NeomycinUndecylenate, Pyrrolnitrin, Siccanin, Tubercidin and Viridin.

35. Antifungal drugs (synthetic), including:

Allylamines such as Naftifine and Terbinafine;

Imidazoles such as Bifonazole, Butoconazole, Chlordantoin,Chlormidazole, Cloconazole, Clotrimazole, Econazole, Enilconazole,Fenticonazole, Isoconazole, Ketoconazole, Miconazole, Omoconazole,Oxiconazole, Nitrate, Sulconazole and Tioconazole;

Triazoles such as Fluconazole, Itraconazole and Terconazole; and

others such as Acrisorcin, Amorolfine, Biphenamine,Bromosalicylchloranilide, Buclosamide, Calcium Propionate, Chlophenesin,Ciclopirox, Cloxyquin, Coparaffinate, Diamthazole, Dihydrochloride,Exalamide, Flucytosine, Halethazole, Hexetidine, Loflucarban, Nifuratel,Potassium Iodide, Propionic Acid, Pyrithione, Salicylanilide, SodiumPropionate, Sulbentine, Tenonitrozole, Tolciclate, Tolindate,Tolnaftate, Tricetin, Ujothion, Undecylenic Acid and Zinc Propionate.

36. Antiglaucoma drugs such as Acetazolamide, Befunolol, Betaxolol,Bupranolol, Carteolol, Dapiprazoke, Dichlorphenamide, Dipivefrin,Epinephrine, Levobunolol, Methazolamide, Metipranolol, Pilocarpine,Pindolol and Timolol.

37. Antigonadotropins such as Danazol, Gestrinone and Paroxypropione.

38. Antigout drugs such as Allopurinol, Carprofen, Colchicine,Probenecid and Sulfinpyrazone.

39. Antihistamines, including:

Alkylamine derivatives such as Acrivastine, Bamipine, Brompheniramine,Chlorpheniramine, Dimethindene, Metron S, Pheniramine, Pyrrobutamine,Thenaldine, Tolpropamine and Triprolidine;

Aminoalkyl ethers such as Bietanautine, Bromodiphenhydramine,Carbinoxamine, Clemastine, Diphenlypyraline, Doxylamine, Embrammine,Medrylamine, Mephenphydramine, p-Methyldiphenhydramine, Orphenadrine,Phenyltoloxamine, Piprinhydrinate and Setasine;

Ethylenediamine derivatives such as Alloclamide, p-Bromtripelennamine,Chloropyramine, Chlorothen, Histapyrrodine, Methafurylene,Methaphenilene, Methapyrilene, Phenbenzamine, Pyrilamine, Talastine,Thenyldiamine, Thonzylamine Hydrochloride, Tripelennamine and Zolamine;

Piperazines such as Cetirizine, Chlorcyclizine, Cinnarizine, Clocinizineand Hydroxyzine;

Tricyclics, including:

Phenothiazines such as Ahistan, Etymemazine, Fenethazine,N-Hydroxyethylpromethazine Chloride, Isopromethazine, Mequitazine,Promethazine, Pyrathiazine and Thiazinamium Methyl Sulfate; and

others such as Azatadine, Clobenzepam, Cyproheptadine, Deptropine,Isothipendyl, Loratadine and Prothipendyl; and

other antihistamines such as Antazoline, Astemizole, Azelastine,Cetoxime, Clemizole, Clobenztropine, Diphenazoline, Diphenhydramine,Fluticasone Propionate, Mebhydroline, Phenindamine, Terfenadine andTritoqualine.

40. Antihyperlipoproteinemics, including:

Aryloxyalkanoic acid derivatives such as Beclorbrate, Bazafibrate,Binifibrate, Ciprofibrate, Clinofibrate, Clofibrate, Clofibric Acid,Etonfibrate, Fenofibrate, Gemfibrozil, Nicofibrate, Pirifibrate,Ronifibrate, Simfibrate and Theofibrate;

Bile acid sequesterants such as Cholestyramine Resin, Colestipol andPolidexide;

HMG CoA reductase inhibitors such as Fluvastatin, Lovastatin,Pravastatin Sodium and Simvastatin;

Nicotinic acid derivatives Aluminum Nicotinate, Acipimox, Niceritrol,Nicoclonate, Nicomol and Oxiniacic Acid;

Thyroid hormones and analogs such as Etiroxate, Thyropropic Acid andThyroxine; and

others such as Acifran, Azacosterol, Benfluorex, â-Benzalbutyramide,Carnitine, Chondroitin Sulfate, Clomestone, Detaxtran, Dextran SulfateSodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Furazbol,Meglutol, Melinamide, Mytatrienediol, Ornithine, ã-Oryzanol, Pantethine,Penataerythritol Tetraacetate, á-Phenylbutyramide, Pirozadil, Probucol,á-Sitosterol, Sultosilic Acid, Piperazine Salt, Tiadenol, Triparanol andXenbucin.

41. Antihypertensive drugs, including:

Arylethanolamine derivatives such as Amosulalol, Bufuralol, Dilevalol,Labetalol, Pronethalol, Sotalol and Sulfinalol;

Aryloxypropanolamine derivatives such as Acebutolol, Alprenolol,Arotinolol, Atenolol, Betaxolol, Bevantolol, Bisoprolol, Bopindolol,Bunitrolol, Bupranolol, Butofilolol, Carazolol, Cartezolol, Carvedilol,Celiprolol, Cetamolol, Epanolol, Indenolol, Mepindolol, Metipranolol,Metoprolol, Moprolol, Nadolol, Nipradilol, Oxprenolol, Penbutolol,Pindolol, Propranolol, Talinolol, Tetraolol, Timolol and Toliprolol;

Benzothiadiazine derivatives such as Althiazide, Bendroflumethiazide,Benzthiazide, Benzylhydrochlorothiazide, Buthiazide, Chlorothiazide,Chlorthalidone, Cyclopenthiazide, Cyclothiazide, Diazoxide, Epithiazide,Ethiazide, Fenquizone, Hydrochlorothiazide, Hydroflumethiazide,Methyclothiazide, Meticrane, Metolazone, Paraflutizide, Polythiazide,Tetrachlormethiazide and Trichlormethiazide;

N-Carboxyalkyl (peptide/lactam) derivatives such as Alacepril,Captopril, Cilazapril, Delapril, Enalapril, Enalaprilat, Fosinopril,Lisinopril, Moveltipril, Perindopril, Quinapril and Ramipril;

Dihydropyridine derivatives such as Amlodipine, Felodipine, Isradipine,Nicardipine, Nifedipine, Nilvadipine, Nisoldipine and Nitrendipine;

Guanidine derivatives such as Bethanidine, Debrisoquin, Guanabenz,Guanacline, Guanadrel, Guanazodine, Guanethidine, Guanfacine,Guanochlor, Guanoxabenz and Guanoxan;

Hydrazines and phthalazines such as Budralazine, Cadralazine,Dihydralazine, Endralazine, Hydracarbazine, Hydralazine, Pheniprazine,Pildralazine and Todralazine;

Imidazole derivatives such as Clonidine, Lofexidine, Phentolamine,Phentolamine Mesylate, Tiamenidine and Tolonidine;

Quaternary ammonium compounds Azamethonium Bromide, ChlorisondamineChloride, Hexamethonium, Pentacynium Bis(methyl sulfate), PentamethoniumBromide, Pentolinium Tartate, Phenactopinium Chloride and TrimethidiunumMethosulfate;

Quinazoline derivatives such as Alfuzosin, Bunazosin, Doxazosin,Prasosin, Terazosin and Trimazosin;

Reserpine derivatives such as Bietaserpine, Deserpidine, Rescinnamine,Reserpine and Syrosingopine;

Sulfonamide derivatives such as Ambuside, Clopamide, Furosemide,Indapamide, Quinethazone, Tripamide and Xipamide; and

others such as Ajmaline, ã-Aminobutyric Acid, Bufeniode, Candesartan,Chlorthalidone, Cicletaine, Ciclosidomine, Cryptenamine Tannates,Eprosartan, Fenoldopam, Flosequinan, Indoramin, Irbesartan, Ketanserin,Losartan, Metbutamate, Mecamylamine, Methyldopa, Methyl 4-Pyridyl KetoneThiosemicarbarzone, Metolazone, Minoxidil, Muzolimine, Pargyline,Pempidine, Pinacidil, Piperoxan, Primaperone, Protoveratrines,Raubasine, Rescimetol, Rilmenidene, Saralasin, Sodium Nitroprusside,Ticrynafen, Trimethaphan Camsylate, Tyrosinase, Urapidil and Valsartan.

42. Antihyperthyroids such as 2-Amino-4-methylthiazole, 2-Aminothiazole,Carbimazole, 3,5-Dibromo-L-tyrosine, 3,5-Diiodotyrosine, Hinderin,Iodine, Iothiouracil, Methimazole, Methylthiouracil, Propylthiouracil,Sodium Perchlorate, Thibenzazoline, Thiobarbital and 2-Thiouracil.

43. Antihypotensive drugs such as Amezinium Methyl Sulfate, AngiotensinAmide, Dimetofrine, Dopamine, Etifelmin, Etilefrin, Gepefrine,Metaraminol, Midodrine, Norepinephrine, Pholedrinead and Synephrine.

44. Antihypothyroid drugs such as Levothyroxine Sodium, Liothyronine,Thyroid, Thyroidin, Thyroxine, Tiratricol and TSH.

45. Anti-Inflammatory (non-steroidal) drugs, including:

Aminoarylcarboxylic acid derivatives such as Enfenamic Acid,Etofenamate, Flufenamic Acid, Isonixin, Meclofenamic Acid, MefanamicAcid, Niflumic Acid, Talniflumate, Terofenamate and Tolfenamic Acid;

Arylacetic acid derivatives such as Acemetacin, Alclofenac, Amfenac,Bufexamac, Cinmetacin, Clopirac, Diclofenac Sodium, Etodolac, Felbinac,Fenclofenac, Fenclorac, Fenclozic Acid, Fentiazac, Glucametacin,Ibufenac, Indomethacin, Isofezolac, Isoxepac, Lonazolac, MetiazinicAcid, Oxametacine, Proglumetacin, Sulindac, Tiaramide, Tolmetin andZomepirac;

Arylbutyric acid derivatives such as Bumadizon, Butibufen, Fenbufen andXenbucin;

Arylcarboxylic acids such as Clidanac, Ketorolac and Tinoridine;

Arylpropionic acid derivatives such as Alminoprofen, Benoxaprofen,Bucloxic Acid, Carprofen, Fenoprofen, Flunoxaprofen, Flurbiprofen,Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Loxoprofen, Miroprofen,Naproxen, Oxaprozin, Piketoprofen, Pirprofen, Pranoprofen, ProtizinicAcid, Suprofen and Tiaprofenic Acid;

Pyrazoles such as Difenamizole and Epirizole;

Pyrazolones such as Apazone, Benzpiperylon, Feprazone, Mofebutazone,Morazone, Oxyphenbutazone, Phenybutazone, Pipebuzone, Propyphenazone,Ramifenazone, Suxibuzone and Thiazolinobutazone;

Salicylic acid derivatives such as Acetaminosalol, Aspirin, Benorylate,Bromosaligenin, Calcium Acetylsalicylate, Diflunisal, Etersalate,Fendosal, Gentisic Acid, Glycol Salicylate, Imidazole Salicylate, LysineAcetylsalicylate, Mesalamine, Morpholine Salicylate, 1-NaphthylSalicylate, Olsalazine, Parsalmide, Phenyl Acetylsalicylate, PhenylSalicylate, Salacetamide, Salicylamine O-Acetic Acid, SalicylsulfuricAcid, Salsalate and Sulfasalazine;

Thiazinecarboxamides such as Droxicam, Isoxicam, Piroxicam andTenoxicam; and

others such as å-Acetamidocaproic Acid, S-Adenosylmethionine,3-Amino-4-hydroxybutyric Acid, Amixetrine, Bendazac, Benzydamine,Bucolome, Difenpiramide, Ditazol, Emorfazone, Guaiazulene, Nabumetone,Nimesulide, Orgotein, Oxaceprol, Paranyline, Perisoxal, Pifoxime,Proquazone, Proxazole and Tenidap.

46. Antimalarial drugs such as Acedapsone, Amodiaquin, Arteether,Artemether, Artemisinin, Artesunate, Bebeerine, Berberine, Chirata,Chlorguanide, Chloroquine, Chlorproguanil, Cinchona, Cinchonidine,Cinchonine, Cycloguanil, Gentiopicrin, Halofantrine, Hydroxychloroquine,Mefloquine Hydrochloride, 3-Methylarsacetin, Pamaquine, Plasmocid,Primaquine, Pyrimethamine, Quinacrine, Quinine, Quinine Bisulfate,Quinine Carbonate, Quinine Dihydrobromide, Quinine Dihydrochloride,Quinine Ethylcarbonate, Quinine Formate, Quinine Gluconate, QuinineHydriodide, Quinine Hydrochloride, Quinine Salicylate, Quinine Sulfate,Quinine Tannate, Quinine Urea Hydrochloride, Quinocide, Quinoline andSodium Arsenate Diabasic.

47. Antimigraine drugs such as Alpiropride, Dihydroergotamine,Eletriptan, Ergocornine, Ergocorninine, Ergocryptine, Ergot, Ergotamine,Flumedroxone acetate, Fonazine, Lisuride, Methysergid(e), Naratriptan,Oxetorone, Pizotyline, Rizatriptan and Sumatriptan.

48. Antinauseant drugs such as Acetylleucine Monoethanolamine,Alizapride, Benzquinamide, Bietanautine, Bromopride, Buclizine,Chlorpromazine, Clebopride, Cyclizine, Dimenhydrinate, Dipheniodol,Domperidone, Granisetron, Meclizine, Methalltal, Metoclopramide,Metopimazine, Nabilone, Ondansteron, Oxypendyl, Pipamazine,Piprinhydrinate, Prochlorperazine, Scopolamine, Tetrahydrocannabinols,Thiethylperazine, Thioproperzaine and Trimethobenzamide.

49. Antineoplastic drugs, including:

Alkylating agents, including:

Alkyl sulfonates such as Busulfan, Improsulfan and Piposulfan;

Aziridines such as Benzodepa, Carboquone, Meturedepa and Uredepa;

Ethylenimines and methylmelamines such as Altretamine, Sulfosamide,Triethylenemelamine, Triethylenephosphoramide,Triethylenethiophosphoramide and Trimethylolomelamine;

Nitrogen mustards such as Chlorambucil, Chlornaphazine,Chclophosphamide, Estramustine, Ifosfamide, Mechlorethamine,Mechlorethamine Oxide Hydrochloride, Melphalan, Novembichin,Phenesterine, Prednimustine, Trofosfamide and Uracil Mustard;

Nitrosoureas such as Carmustine, Chlorozotocin, Fotemustine, Lomustine,Nimustine and Ranimustine; and

others such as Camptothecin, Dacarbazine, Mannomustine, Mitobronitol,Mitolactol and Pipobroman;

Antibiotics such as Aclacinomycins, Actinomycin F₁, Anthramycin,Azaserine, Bleomycins, Cactinomycin, Carubicin, Carzinophilin,Chromomycins, Dactinomycin, Daunorubicin, 6-Diazo-5-oxo-L-norleucine,Doxorubicin, Epirubicin, Mitomycins, Mycophenolic Acid, Nogalamycin,Olivomycins, Peplomycin, Plicamycin, Porfiromycin, Puromycin,Rufocromomycin, Streptonigrin, Streptozocin, Tubercidin, Ubenimex,Zinostatin and Zorubicin;

Antimetabolites, including:

Folic acid analogs such as Denopterin, Methotrexate, Pteropterin andTrimetrexate;

Purine analogs such as Fludarabine, 6-Mercaptopurine, Thiamiprine andThioguanaine; and

Pyrimidine analogs such as Ancitabine, Azacitidine, 6-Azauridine,Carmofur, Cytarabine, Doxifluridine, Enocitabine, Floxuridine,Fluroouracil and Tegafur;

Enzymes such as L-Asparaginase; and

others such as Aceglatone, Amsacrine, Bestrabucil, Bisantrene,Bryostatin 1, Carboplatin, Cisplatin, Defofamide, Demecolcine,Diaziquone, Dolastatins, Elfornithine, Elliptinium Acetate, Etoglucid,Etoposide, Gallium Nitrate, Hydroxyurea, Interferon-á, Interferon-â,Interferon-ã, Interleukine-2, Lentinan, Letrozole, Lonidamine,Mitoguazone, Mitoxantrone, Mopidamol, Nitracrine, Pentostatin, Phenamet,Pirarubicin, Podophyllinicc Acid, 2-Ethythydrazide, Polynitrocubanes,Procarbazine, PSK7, Razoxane, Sizofiran, Spirogermanium, Symplostatin 1,Taxol, Teniposide, Tenuazonic Acid, Triaziquone,2.2′.2″-Trichlorotriethylamine, Urethan, Vinblastine, Vincristine,Vindesine and Vinorelbine.

50. Antineoplastic (hormonal) drugs, including:

Androgens such as Calusterone, Dromostanolone Propionate, Epitiostanol,Mepitiostane and Testolactone;

Antiadrenals such as Aminoglutethimide, Mitotane and Trilostane;

Antiandrogens such as Flutamide and Nilutamide; and

Antiestrogens such as Tamoxifen and Toremifene.

51. Antineoplastic adjuncts including folic acid replenishers such asFrolinic Acid.

52. Antiparkinsonian drugs such as Amantadine, Apomorphine, Benserazide,Bietanautine, Biperiden, Bromocriptine, Budipine, Cabergoline,Carbidopa, Deprenyl (a/k/a L-deprenyl, L-deprenil, L-deprenaline andselegiline), Dexetimide, Diethazine, Diphenhydramine, Droxidopa,Ethopropazine, Ethylbenzhydramine, Levodopa, Naxagolide, Pergolide,Piroheptine, Pramipexole, Pridinol, Prodipine, Quinpirole, Remacemide,Ropinirole, Terguride, Tigloidine and Trihexyphenidyl Hydrochloride.

53. Antipheochromocytoma drugs such as Metyrosine, Phenoxybenzamine andPhentolamine.

54. Antipneumocystis drugs such as Effornithine, Pentamidine andSulfamethoxazole.

55. Antiprostatic hypertrophy drugs such as Gestonorone Caproate,Mepartricin, Oxendolone and Proscar7.

56. Antiprotozoal drugs (Leshmania) such as Antimony Sodium Gluconate,Ethylstibamine, Hydroxystilbamidine, N-Methylglucamine, Pentamidine,Stilbamidine and Urea Stibamine.

57. Antiprotozoal drugs (Trichomonas) such as Acetarsone, Aminitrozole,Anisomycin, Azanidazole, Forminitrazole, Furazolidone, Hachimycin,Lauroguadine, Mepartricin, Metronidazole, Nifuratel, Nifuroxime,Nimorazole, Secnidazole, Silver Picrate, Tenonitrozole and Tinidazole.

58. Antiprotozoal drugs (Trypanosma) such as Benznidazole, Eflornithine,Melarsoprol, Nifurtimox, Oxophenarsine, Hydrochloride, Pentamidine,Propamidine, Puromycin, Quinapyramine, Stilbamidine, Suramin Sodium,Trypan Red and Tryparasmide.

59. Antipuritics such as Camphor, Cyproheptadine, Dichlorisone, Glycine,Halometasone, 3-Hydroxycamphor, Menthol, Mesulphen, Methdilazine,Phenol, Polidocanol, Risocaine, Spirit of Camphor, Thenaldine,Tolpropamine and Trimeprazine.

60. Antipsoriatic drugs such as Acitretin, Ammonium Salicylate,Anthralin, 6-Azauridine, Bergapten(e), Chrysarobin, Etretinate andPyrogallol.

61. Antipsychotic drugs, including:

Butyrophenones such as Benperidol, Bromperidol, Droperidol, Fluanisone,Haloperidol, Melperone, Moperone, Pipamperone, Sniperone, Timiperone andTrifluperidol;

Phenothiazines such as Acetophenazine, Butaperazine, Carphenazine,Chlorproethazine, Chlorpromazine, Clospirazine, Cyamemazine, Dixyrazine,Fluphenazine, Imiclopazine, Mepazine, Mesoridazine, Methoxypromazine,Metofenazate, Oxaflumazine, Perazine, Pericyazine, Perimethazine,Perphenazine, Piperacetazine, Pipotiazine, Prochlorperazine, Promazine,Sulforidazine, Thiopropazate, Thioridazine, Trifluoperazine andTriflupromazine;

Thioxanthenes such as Chlorprothixene, Clopenthixol, Flupentixol andThiothixene;

other tricyclics such as Benzquinamide, Carpipramine, Clocapramine,Clomacran, Clothiapine, Clozapine, Opipramol, Prothipendyl,Tetrabenazine, and Zotepine; and

others such as Alizapride, Amisulpride, Buramate, Fluspirilene,Molindone, Penfluridol, Pimozide, Spirilene and Sulpiride.

62. Antipyretics such as Acetaminophen, Acetaminosalol, Acetanilide,Aconine, Aconite, Aconitine, Alclofenac, Aluminum Bis(acetylsalicylate),Aminochlorthenoxazin, Aminopyrine, Aspirin, Benorylate, Benzydamine,Berberine, p-Bromoacetanilide, Bufexamac, Bumadizon, CalciumAcetysalicylate, Chlorthenoxazin(e), Choline Salicylate, Clidanac,Dihydroxyaluminum Acetylsalicylate, Dipyrocetyl, Dipyrone, Epirizole,Etersalate, Imidazole Salicylate, Indomethacin, Isofezolac,p-Lactophenetide, Lysine Acetylsalicylate, Magnesium Acetylsalicylate,Meclofenamic Acid, Morazone, Morpholine Salicylate, Naproxen,Nifenazone, 5′-Nitro-2′-propoxyacetanilide, Phenacetin, Phenicarbazide,Phenocoll, Phenopyrazone, Phenyl Acetylsalicylate, Phenyl Salicylate,Pipebuzone, Propacetamol, Propyphenazone, Ramifenazone, Salacetamide,Salicylamide O-Acetic Acid, Sodium Salicylate, Sulfamipyrine,Tetrandrine and Tinoridine.

63. Antirickettsial drugs such as p-Aminobenzoic Acid, Chloramphenicol,Chloramphenicol Palmitate, Chloramphenicol Pantothenate andTetracycline.

64. Antiseborrheic drugs such as Chloroxine, 3-O-LauroylpyridoxolDiacetate, Piroctone, Pyrithione, Resorcinol, Selenium Sulfides andTioxolone.

65. Antiseptics, including:

Guanidines such as Alexidine, Ambazone, Chlorhexidine and Picloxydine;

Halogens and halogen compounds such as Bismuth Iodide Oxide, BismuthIodosubgallate, Bismuth Tribromophenate, Bornyl Chloride, CalciumIodate, Chlorinated Lime, Cloflucarban, Flurosalan, Iodic Acid, Iodine,Iodine Monochloride, Iodine Trichloride, Iodoform, MethenamineTetraiodine, oxychlorosene, Povidone-Iodine, Sodium Hypochlorite, SodiumIodate, Symclosene, Thymol Iodide, Triclocarban, Triclosan andTroclosene Potassium;

Mercurial compounds such as Hydragaphen, Meralein Sodium, Merbromin,Mercuric Chloride, Mercuric Chloride, Ammoniated, Mercuric Sodiump-Phenolsulfonate, Mercuric Succinimide, Mercuric Sulfide, Red,Mercurophen, Mercurous Acetate, Mercurous Chloride, Mercurous Iodide,Nitromersol, Potassium Tetraiodomercurate(II), PotassiumTriiodomercurate(II) Solution, Thimerfonate Sodium and Thimerosal;

Nitrofurans such as Furazolidone, 2-(Methoxymethyl)-5-nitrofuran,Nidroxyzone, Nifuroxime, Nifurzide and Nitrofurazone;

Phenols such as Acetomeroctol, Bithionol, Cadmium Salicylate, Carvacrol,Chloroxylenol, Clorophene, Cresote, Cresol(s), p-Cresol, Fenticlor,Hexachlorophene, 1-Napthyl Salicylate, 2-Napthyl Salicylate,2,4,6-Tribromo-m-cresol, and 3′, 4′,5-Trichlorosalicylanilide;

Quinolines such as Aminoquinuride, Benzoxiquine, Broxyquinoline,Chloroxine, Chlorquinaldol, Cloxyquin, Ethylhydrocupreine, Euprocin,Halquinol, Hydrastine, 8-Hydroxquinoline, 8-Hydroxquinoline Sulfate andIodochlorhydroxyquin; and

others such as Aluminum Acetate Solution, Aluminum Subacetate Solution,Aluminum Sulfate, 3-Amino-4-hydroxybutyric Acid, Boric Acid,Chlorhexidine, Chloroazodin, m-Cresyl Acetate, Cupric Sulfate,Dibromopropamidine, Ichthammol, Negatol7, Noxytiolin, Ornidazole,â-Propiolactone, á-Terpineol.

66. Antispasmodic drugs such as Alibendol, Ambucetamide, Aminopromazine,Apoatropine, Bevonium Methyl Sulfate, Bietamiverine, Butaverine,Butropium Bromide, N-Butylscopolammonium Bromide, Caroverine,Cimetropium Bromide, Cinnamedrine, Clebopride, Coniine Hydrobromide,Coniine Hydrochloride, Cyclonium Iodide, Difemerine, Diisopromine,Dioxaphetyl Butyrate, Diponium Bromide, Drofenine, Emepronium Bromide,Ethaverine, Feclemine, Fenalamide, Fenoverine, Fenpiprane, FenpiveriniumBromide, Fentonium Bromide, Flavoxate, Flopropione, Gluconic Acid,Guaiactamine, Hydramitrazine, Hymecromone, Leiopyrrole, Mebeverine,Moxaverine, Nafiverine, Octamylamine, Octaverine, Pentapiperide,Phenamacide Hydrochloride, Phloroglucinol, Pinaverium Bromide,Piperilate, Pipoxolan Hydrochloride, Pramiverin, Prifinium Bromide,Properidine, Propivane, Propyromazine, Prozapine, Racefemine,Rociverine, Spasmolytol, Stilonium Iodide, Sultroponium, TiemoniumIodide, Tiquizium Bromide, Tiropramide, Trepibutone, Tricromyl,Trifolium, Trimebutine, N,N-lTrimethyl-3,3-diphenyl-propylamine,Tropenzile, Trospium Chloride and Xenytropium Bromide.

67. Antithrombotic drugs such as Anagrelide, Argatroban, Cilostazol,Chrysoptin, Daltroban, Defibrotide, Enoxaparin, Fraxiparine7, Indobufen,Lamoparan, Ozagrel, Picotamide, Plafibride, Reviparin, Tedelparin,Ticlopidine, Triflusal and Warfarin.

68. Antitussive drugs such as Allocamide, Amicibone, Benproperine,Benzonatate, Bibenzonium Bromide, Bromoform, Butamirate, Butethamate,Caramiphen Ethanedisulfonate, Carbetapentane, Chlophedianol, Clobutinol,Cloperastine, Codeine, Codeine Methyl Bromide, Codeine N-Oxide, CodeinePhosphate, Codeine Sulfate, Cyclexanone, Dextromethorphan, DibunateSodium, Dihydrocodeine, Dihydrocodeinone Enol Acetate, Dimemorfan,Dimethoxanate, á,á-Diphenyl-2-piperidinepropanol, Dropropizine,Drotebanol, Eprazinone, Ethyl Dibunate, Ethylmorphine, Fominoben,Guiaiapate, Hydrocodone, Isoaminile, Levopropoxyphene, Morclofone,Narceine, Normethadone, Noscapine, Oxeladin, Oxolamine, Pholcodine,Picoperine, Pipazethate, Piperidione, Prenoxdiazine Hydrochloride,Racemethorphan, Taziprinone Hydrochloride, Tipepidine and Zipeprol.

69. Antiulcerative drugs such as Aceglutamide Aluminum Complex,å-Acetamidocaproic Acid Zinc Salt, Acetoxolone, Arbaprostil, BenexateHydrochloride, Bismuth Subcitrate Sol (Dried), Carbenoxolone, Cetraxate,Cimetidine, Enprostil, Esaprazole, Famotidine, Ftaxilide, Gefarnate,Guaiazulene, Irsogladine, Misoprostol, Nizatidine, Omeprazole,Ornoprostil, ã-Oryzanol, Pifarnine, Pirenzepine, Plaunotol, Ranitidine,Rioprostil, Rosaprostol, Rotraxate, Roxatidine Acetate, Sofalcone,Spizofurone, Sucralfate, Teprenone, Trimoprostil, Thrithiozine,Troxipide and Zolimidine.

70. Antiurolithic drugs such as Acetohydroxamic Acid, Allopurinol,Potassium Citrate and Succinimide.

71. Antivenin drugs such as Lyovac7 Antivenin.

72. Antiviral drugs, including:

Purines and pyrimidinones such as Acyclovir, Cytarabine,Dideoxyadenosine, Dideoxycytidine, Dideoxyinosine, Edoxudine,Floxuridine, Ganciclovir, Idoxuridine, Inosine Pranobex, MADU,Penciclovir, Trifluridine, Vidrarbine and Zidovudiine; and

others such as Acetylleucine Monoethanolamine, Amantadine, Amidinomycin,Cosalane, Cuminaldehyde Thiosemicarbzone, Foscarnet Sodium, Imiquimod,Interferon-á, Interferon-â, Interferon-ã, Kethoxal, Lysozyme,Methisazone, Moroxydine, Podophyllotoxin, Ribavirin, Rimantadine,Stallimycin, Statolon, Tromantadine and Xenazoic Acid.

73. Anxiolytic drugs, including:

Arylpiperazines such as Buspirone, Gepirone, Isapirone and Tondospirone.

Benzodiazepine derivatives such as Alprazolam, Bromazepam, Camazepam,Chlordiazepoxide, Clobazam, Clorazepate, Chotiazepam, Cloxazolam,Diazepam, Ethyl Loflazepate, Etizolam, Fluidazepam, Flutazolam,Flutoprazepam, Halazepam, Ketazolam, Lorazepam, Loxapine, Medazepam,Metaclazepam, Mexazolam, Nordazepam, Oxazepam, Oxazolam, Pinazepam,Prazepam and Tofisopam;

Carbamates such as Cyclarbamate, Emylcamate, Hydroxyphenamate,Meprobamate, Phenprobamate and Tybamate; and

others such as Alpidem, Benzoctamine, Captodiamine, Chlormezanone,Etifoxine, Flesinoxan, Fluoresone, Glutamic Acid, Hydroxyzine,Lesopitron, Mecloralurea, Mephenoxalone, Mirtazepine, Oxanamide,Phenaglycodol, Suriclone and Zatosetron.

74. Benzodiazepine antagonists such as Flumazenil.

75. Bronchodilators, including:

Ephedrine derivatives such as Albuterol, Bambuterol, Bitolterol,Carbuterol, Clenbuterol, Clorprenaline, Dioxethedrine, Ephedrine,Epiniphrine, Eprozinol, Etafedrine, Ethylnorepinephrine, Fenoterol,Hexoprenaline, Isoetharine, Isoproterenol, Mabuterol, Metaproterenol,N-Methylephedrine, Pirbuterol, Procaterol, Protokylol, Reproterol,Rimiterol, Salmeterol, Soterenol, Terbutaline and Tulobuterol;

Quaternary ammonium compounds such as Bevonium Methyl Sulfate,Clutropium Bromide, Ipratropium Bromide and Oxitropium Bromide;

Xanthine derivatives such as Acefylline, Acefylline Piperazine,Ambuphylline, Aminophylline, Bamifylline, choline Theophyllinate,Doxofylline, Dyphylline, Enprofylline, Etamiphyllin, Etofylline,Guaithylline, Proxyphylline, Theobromine, 1-Theobromineacetic Acid andTheophylline; and

others such as Fenspiride, Medibazine, Montekulast, Methoxyphenanime,Tretoquinol and Zafirkulast.

76. Calcium channel blockers, including:

Arylalkylamines such as Bepridil, Ditiazem, Fendiline, Gallopanil,Prenylamine, Terodiline and Verapamil;

Dihydropyridine derivatives such as Felodipine, Isradipine, Nicardipine,Nifedipine, Nilvadipine, Nimodipine, Nisoldipine and Nitrendipine;

Piperazine derivatives such as Cinnarizine, Flunarisine and Lidoflazine;and

others such as Bencyclane, Etafenone and Perhexiline.

77. Calcium regulators such as Calcifediol, Calcitonin, Calcitriol,Clodronic Acid, Dihydrotachysterol, Elcatonin, Etidronic Acid,Ipriflavone, Pamidronic Acid, Parathyroid Hormone and TeriparatideAcetate.

78. Cardiotonics such as Acefylline, Acetyldigititoxins,2-Amino-4-picoline, Amrinone, Benfurodil Hemisuccinate, Buclasdesine,Cerberoside, Camphotamide, Convallatoxin, Cymarin, Denopamine,Deslanoside, Ditalin, Digitalis, Digitoxin, Digoxin, Dobutamine,Dopamine, Dopexamine, Enoximone, Erythrophleine, Fenalcomine, Gitalin,Gitoxin, Glycocyamine, Heptaminol, Hydrastinine, Ibopamine, Lanotodises,Metamivam, Milrinone, Neriifolin, Oleandrin, Ouabain, Oxyfedrine,Prenalterol, Proscillaridin, Resibufogenin, Scillaren, Scillarenin,Strophanthin, Sulmazole, Theobromine and Xamoterol.

79. Chelating agents such as Deferozmine, Ditiocarb Sodium, EdetateCalcium Disodium, Edetate Disodium, Edeate Sodium, Edetate Trisodium,Penicillamine, Pentetate Calcium Trisodium, Pentectic Acid, Succimer andTrientine;

80. Cholecystokinin antagonists such as Proglumide.

81. Cholelitholytic agents such as Chenodiol, Methyl tert-Butyl Ether,Monooctanoin and Ursodiol.

82. Choleretics such as Alibendol, Anethole Trithion, Azintamide, CholicAcid, Cicrotoic Acid, Clanobutin, Cyclobutyrol, Cyclovalone, Cynarin(e),Dehydrocholic Acid, Deoxycholic Acid, Dimecrotic Acid, á-EthylbenzylAlcohol, Exiproben, Feguprol, Fencibutirol, Fenipentol, Florantyrone,Hymecromone, Menbutone, 3-(o-Methoxyphenyl)-2-phenylacrylic Acid,Metochalcone, Moquizone, Osalmid, Ox Bile Extract, 4.4′-Oxydi-2-butanol,Piprozolin, Prozapine, 4-Salicyloylmorpholine, Sincalide, TaurocholicAcid, Timonacic, Tocamphyl, Trepibutone and Vanitiolide.

83. Cholinergic agents such as Aceclidine, Acetylcholine Bromide,Acetylcholide Chloride, Aclatonium Napadisilate, Benzpyrinium Bromide,Bethanechol chloride, Carbachol, Carpronium chloride, DemecariumBromide, Dexpanthenol, Diisopropyl Paraoxon, Echothiophate Iodide,Edrophomium chloride, Eseridine, Furtrethonium, Isoflurophate,Methacholine chloride, Muscarine, Neostigmine, Oxapropanium Iodide,Physostigmine and Pyridostigmine Bromide.

84. Cholinesterase inhibitors such as Ambenonium Chloride, DistigmineBromide and Galanthamine.

85. Cholinesterase reactivators such as Obidoximine Chloride andPralidoxime Chloride.

86. Central nervous system stimulants and agents such as Amineptine,Amphetimine, Amphetaminil, Bemegride, Benzphetamine, Brucine, Caffeine,Chlorphentermine, Clofenciclan, Clortermine, Coca, Demanyl Phosphate,Dexoxadrol, Dextroamphetamine Sulfate, Diethlpropion,N-Ethylamphetamine, Ethamivan, Etifelmin, Etryptamine, Fencamfamine,Fenethylline, Fenosolone, Flurothyl, Galanthamine, Hexacyclonate Sodium,Homocamfin, Mazindol, Megexamide, Methamphetamine, Methylphenidate,Nikethamide, Pemoline, Pentylenetetrazole, Phenidimetrazine,Phenmetrazine, Phentermine, Picrotoxin, Pipradrol, Prolintane andPyrovalerone.

87. Decongestants such as Amidephrine, Cafaminol, Cyclopentamine,Ephedrine, Epinephrine, Fenoxazoline, Indanazoline, Metizoline,Naphazoline, Nordefrin Hydrochloride, Octodrine, Oxymetazoline,Phenylephrine Hydrochloride, Phenylpropanolamine Hydrochloride,Phenylpropylmethylamine, Propylhexedrine, Pseudoephedrine,Tetrahydrozoline, Tymazoline and Xylometazoline.

88. Dental agents, including:

Bisphosphonates (anti-periodontal disease and bone resorption) such asAlendronate, Clodronate, Etidronate, Pamidronate and Tiludronate;

Carries Prophylactics such as Arginine and Sodium Fluoride;Desensitizing Agents such as Potassium Nitrate and Citrate Oxalate.

89. Depigmentors such as Hydroquinine, Hydroquinone and Monobenzone.

90. Diuretics, including:

organomercurials such as Chlormerodrin, Meralluride, Mercamphamide,Mercaptomerin Sodium, Mercumallylic Acid, Mercumatilin Sodium, MercurousChloride and Mersalyl;

Pteridines such as Furterene and Triamterene;

Purines such as Acefylline, 7-Morpholinomethyltheophylline, Pamabrom,Protheobromine and Theobromine;

Steroids such as Canrenone, Oleandrin and Spironolactone;

Sulfonamide derivatives such as Acetazolmide, Ambuside, Azosemide,Bumetanide, Butazolamide, Chloraminophenamide, Clofenamide, Clopamide,Clorexolene, Diphenylmethane-4.4′-disulfonamide, Disulfamide,Ethoxzolamide, Furosemide, Indapamide, Mefruside, Methazolamide,Piretanide, Quinethazone, Torsemide, Tripamide and Xipamide;

Uracils such as Aminometradine and Amisometradine;

others such as Amanozine, Amiloride, Arbutin, Chlorazanil, EthacrynicAcid, Etozolin, Hydracarbazine, Isosorbide, Mannitol, Metochalcone,Muzolimine, Perhexiline, Ticrynafen and Urea.

91. Dopamine receptor agonists such as Bromocriptine, Dopexamine,Fenoldopam, Ibopamine, Lisuride, Naxagolide and Pergolide.

92. Ectoparasiticides such as Amitraz, Benzyl Benzoate, Carbaryl,Crotamiton, DDT, Dixanthogen, Isobornyl Thiocyanoacetate—Technical, LimeSulfurated Solution, LIndane, Malathion, Mercuric Oleate, Mesulphen andSulphur—Pharmaceutical.

93. Enzymes, including:

Digestive enzymes such as á-Amylase (Swine Pancreas), Lipase,Pancrelipase, Pepsin and Rennin;

Mucolytic enzymes such as Lysozyme;

Penicillin inactivating enzymes such as Penicillinase; and

Proteolytic enzymes such as Collagenase, Chymopapain, Chymotrypsins,Papain and Trypsin.

94. Enzyme inducers (hepatic) such as Flumecinol.

95. Estrogens (non-steroidal) such as Benzestrol, Broparoestrol,Chlorotrianisene, Dienestrol, Diethylstilbestrol, DiethylstilbestrolDiproprionate, Dimestrol, Fosfestrol, Hexestrol, Methallenestril andMethestrol.

96. Gastric secretion inhibitors such as Enterogastrone and Octreotide.

97. Glucocorticoids such as 21-Acetoxyprefnenolone, Aalclometasone,Algestone, Amicinonide, Beclomethasone, Betamethasone, Budesonide,Chloroprednisone, Clobetasol, Blovetasone, Clocortolone, Cloprednol,Corticosterone, Cortisone, Cortivazol, Deflazacort, Desonide,Desoximetasone, Dexamethasone, Diflorasone, Diflucortolone,Difluprednate, Enoxolone, Fluazacort, Flucloronide, Flumehtasone,Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortin Butyl,Fluocortolone, Fluorometholone, Fluperolone Acetate, FluprednideneAcetate, Fluprednisolone, Flurandrenolide, Formocortal, Halcinonide,Halometasone, Halopredone Acetate, Hydrocortamate, Hydrocortisone,Hydrocortisone Acetate, ydrocortisone Phosphate, Hydrocortisone21-Sodium Succinate, Hydrocortisone Tebutate, Mazipredone, Medrysone,Meprednisone, Methyolprednisolone, Mometasone Furoate, Paramethasone,Prednicarbate, Prednisolone, Prednisolone 21-Diethylaminoacetate,Prednisone Sodium Phosphate, Prednisolone Sodium Succinate, PrednisoloneSodium 21-m-Sulfobenzoate, Prednisolone 21-Stearoylglycolate,Prednisolone Tebutate, Prednisolone 21-Trimethylacetate, Prednisone,Prednival, Prednylidene, Prednylidene 21-Diethylaminoacetate,Tixocortal, Triamcinolone, Triamcinolone Acetonide, TriamcinoloneBenetonide and Triamcinolone Hexacetonide.

98. Gonad-Stimulating principles such as Buserelin, Clomiphene,Cyclofenil, Epimestrol, FSH, HCG and LH-RH.

99. Gonadotropic hormones such as LH and PMSG.

100. Growth hormone inhibitors such as Octreotide and Somatostatin.

101. Growth hormone releasing factors such as Semorelin.

102. Growth stimulants such as Somatotropin.

103. Hemolytic agents such as Phenylhydrazine and PhenylhydrazineHydrochloride.

104. Heparin antagonists such as Hexadimethrine Bromide and Protamines.

105. Hepatoprotectants such as S-Adenosylmethionine, Betaine, Catechin,Citolone, Malotilate, Orazamide, Phosphorylcholine, Protoporphyrin IX,Silymarin-Group, Thiotic Acid and Tiopronin.

106. Immunomodulators such as Amiprilose, Bucillamine, Ditiocarb Sodium,Inosine Pranobex, Interferon-y, Interleukin-2, Lentinan, Muroctasin,Platonin, Procodazole, Tetramisole, Thymomodulin, Thymopentin andUbenimex.

107. Immunosuppressants such as Azathioprine, Cyclosporins andMizoribine.

108. Ion exchange resins such as Carbacrylic Resins, CholestyramineResin, Colestipol, Polidexide, Resodec and Sodium Polystyrene Sulfonate.

109. Lactation stimulating hormone such as Prolactin.

110. LH-RH agonists such as Buserelin, Goserelin, Goserelin Acetate,Leuprolide, Nafarelin, and Triptorelin.

111. Lipotropic agents such as N-Acetylmethionine, Choline Chloride,Choline Dehydrocholate, Choline Dihydrogen Citrate, Inositol, Lecithinand Methionine.

112. Lupus erythematosus suppressants such as Bismuth SodiumTriglycollamate, Bismuth Subsalicylate, Chloroquine andHydroxychloroquine.

113. Mineralcorticoids such as Aldosterone, Deoxycorticosterone,Deoxycorticosterone Acetate and Fludrocortisone.

114. Miotic drugs such as Carbachol, Physostigmine, Pilocarpine andPilocarpus.

115. Monoamine oxidase inhibitors such as Deprenyl, Iproclozide,Iproniazid, Isocarboxazid, Moclobemide, Octomoxin, Pargyline,Phenelzine, Phenoxypropazine, Pivalylbenzhydrazine, Prodipine,Toloxatone and Tranylcypromine.

116. Mucolytic agents such as Acetylcysteine, Bromhexine, Carbocysteine,Domiodol, Letosteine, Lysozyme, Mecysteine Hydrochloride, Mesna,Sobrerol, Stepronin, Tiopronin and Tyloxapol.

117. Muscle relaxants (skeletal) such as Afloqualone, Alcuronium,Atracurium Besylate, Baclofen, Benzoctamine, Benzoquinonium Chloride,C-Calebassine, Carisoprodol, Chlormezanone, Chlorphenesin Carbamate,Chlorproethazine, Chlozoxazone, Curare, Cyclarbamate, Cyclobenzaprine,Dantrolene, Decamethonium Bromide, Diazepam, Eperisone, FazadiniumBromide, Flumetramide, Gallamine Triethiodide, Hexacarbacholine Bromide,Hexafluorenium Bromide, Idrocilamide, Lauexium Methyl Sulfate,Leptodactyline, Memantine, Mephenesin, Mephenoxalone, Metaxalone,Methocarbamol, Metocurine Iodide, Nimetazepam, Orphenadrine, PancuroniumBromide, Phenprobamate, Phenyramidol, Pipecurium Bromide, Promoxolane,Quinine Sulfate, Styramate, Succinylcholine Bromide, SuccinylcholineChloride, Succinylcholine Iodine, Suxethonium Bromide, Tetrazepam,Thiocolchicoside, Tizanidine, Tolperisone, Tubocurarine Chloride,Vecuronium Bromide and Zoxolamine.

118. Narcotic antagonists such as Amiphenazole, Cyclazocine,Levallorphan, Nadide, Nalmfene, Nalorphine, Nalorphine Dinicotinate,Naloxone and Naltrexone.

119. Neuroprotective agents such as Dizocilpine.

120. Nootropic agents such as Aceglutamide, Acetylcarnitine, Aniracetam,Bifematlane, Exifone, Fipexide, Idebenone, Indeloxazune Hydrochloride,Nizofenone, Oxiracetam, Piracetam, Propentofylline, Pyritinol andTacrine.

121. Ophthalmic agents such as 15-ketoprostaglandins.

122. Ovarian hormone such as Relaxin.

123. Oxytocic drugs such as Carboprost, Cargutocin, Deaminooxytocin,Ergonovine, Gemeprost, Methylergonovine, Oxytocin, Pituitary(Posterior), Prostaglandin E₂, Prostaglandin F_(2á) and Sparteine.

124. Pepsin inhibitors such as Sodium Amylosulfate.

125. Peristaltic stimulants such as Cisapride.

126. Prolactin inhibitors such as Metergoline.

127. Prostaglandins and prostaglandin analogs such as Arbaprostil,Carboprost, Enprostil, Bemeprost, Limaprost, Misoprostol, Ornoprostil,Prostacyclin, Prostaglandin E₁, Prostaglandin E₂, Prostagland in F_(2á)Rioprostil, Rosaprostol, Sulprostone and Trimoprostil.

128. Protease inhibitors such as Aprotinin, Camostat, Gabexate andNafamostat.

129. Respiratory stimulants such as Almitrine, Bemegride, CarbonDioxide, Cropropamide, Crotethamide, Dimefline, Dimorpholamine,Doxapram, Ethamivan, Fominoben, Lobeline, Mepixanox, Metamivam,Nikethamide, Picrotoxin, Pimeclone, Pyridofylline, Sodium Succinate andTacrine.

130. Sclerosing agents such as Ethanolamine, Ethylamine, 2-HexyldecanoicAcid, Polidocanol, Quinine Bisulfate, Quinine Urea Hydrochloride, SodiumRicinoleate, Sodium Tetradecyl Sulfate and Tribenoside.

131. Sedatives and hypnotics, including:

Acyclic ureides such as Acecarbromal, Apronalide, Bomisovalum, Capuride,Carbromal and Ectylurea;

Alcohols such as Chlorhexadol, Ethchlorvynol, Meparfynol,4-Methyl-5-thiazoleethanol, tert-Pentyl Alcohol and2,2,2-Trichloroethanol;

Amides such as Butoctamide, Diethylbromoacetamide, Ibrotamide,Isovaleryl Diethylamide, Niaprazine, Tricetamide, Trimetozine, Zolpidemand Zopiclone;

Barbituric acid derivatives such as Allobarbital, Amobarbital,Aprobarbital, Barbital, Brallabarbital, Butabarbital Sodium, Butalbital,Butallylonal, Butethal, Carbubarb, Cyclobarbital, Cyclopentobarbital,Enallylpropymal, 5-Ethyl-5-(1-piperidyl) barbituric Acid,5-Furfuryl-5-isopropylbarbituric Acid, Heptabarbital, Hexethal Sodium,Hexobarbital, Mephobarbital, Methitural, Narcobarbital, Nealbarbital,Pentobarbital Sodium, Phenallymal, Phenobarbital, Phenobarbital Sodium,Phenylmethylbarbituric Acid, Probarbital, Propallylonal, Proxibarbal,Reposal, Secobarbital Sodium, Talbutal, Tetrabarbital, VinbarbitalSodium and Vinylbital;

Benzodiazepine derivatives such as Brotizolam, Doxefazepam, Estazolam,Flunitrazepam, Flurazepam, Haloxazolam, Loprazolam, Lormetazepam,Nitrazepam, Quazepam, Temazepam and Triazolam;

Bromides such as Ammonium Bromide, Calcium Bromide, CalciumBromolactobionate, Lithium Bromide, Magnesium Bromide, Potassium Bromideand Sodium Bromide;

Carbamates such as Amyl Carbamate—Tertiary, Ethinamate, Hexaprpymate,Meparfynol Carbamate, Novonal and Tricholorourethan;

Chloral derivatives such as Carbocloral, Chloral Betaine, ChloralFormamide, Chloral Hydrate, Chloralantipyrine, Dichloralphenazone,Pentaerythritol Chloral and Triclofos;

Piperidinediones such as Glutehimide, Methyprylon, Piperidione,Pyrithyldione, Taglutimide and Thalidomide;

Quinazolone derivatives such as Etaqualone, Mecloqualone andMethaqualone; and

others such as Acetal, Acetophenone, Aldol, Ammonium Valerate,Amphenidone, d-Bornyl á-Bromoisovalerate, d-Bornyl Isovalerate,Bromoform, Calcium 2-Ethylbutanoate, Carfinate, á-Chlorolose,Clomethiazole, Cypripedium, Doxylamine, Etodroxizine, Etomidate,Fenadiazole, Homofenazine, Hydrobromic Acid, Mecloxamine, MenthylValerate, Opium, Paraldehyde, Perlapine, Propiomazine, Rilmazafone,Sodium Oxybate, Sulfonethylmethane and Sulfonmethane.

132. Thrombolytic agents such as APSAC, Plasmin, Pro-Urokinase,Streptokinase, Tissue Plasminogen Activator and Urokinase;

133. Thyrotropic hormones such as TRH and TSH.

134. Uricosurics such as Benzbromarone, Ethebenecid, Orotic Acid,Oxycinchophen, Probenecid, Sulfinpyrazone, Ticrynafen and Zoxazolamine.

135. Vasodilators (cerebral) such as Bencyclane, Cinnarizine,Citicoline, Cyclandelate, Ciclonicate, Diisopropylamine Dichloractetate,Eburnamonine, Fenoxedil, Flunarizine, Ibudilast, Ifenprodil, Nafronyl,Nicametate, Nicergoline, Nimodipine, Papaverine, Pentifylline,Tinofedrine, Vincamine, Vinpocetine and Viquidil.

136. Vasodilators (coronary) such as Amotriphene, Bendazol, BenfurodilHemisuccinate, Benziodarone, Chloacizine, Chromonar, Clobenfurol,Clonitrate, Dilazep, Dipyridamole, Droprenilamine, Efloxate, Erythritol,Erythrityl Tetranitrate, Etafenone, Fendiline, Floredil, Ganglefene,Hexestrol Bis(β-diethylaminoethyl ether), Hexobendine, Itramin Tosylate,Khellin, Lidoflazine, Mannitol Hexanitrate, Medibazine, Nicorandil,Nitroglycerin, Pentaerythritol Tetranitrate, Pentrinitrol, Perhexiline,Pimefylline, Prenylamine, Propatyl Nitrate, Pyridofylline, Trapidil,Tricromyl, Trimetazidine, Trolnitrate Phosphate and Visnadine.

137. Vasodilators (peripheral) such as Aluminum Nicotinate, Bamethan,Bencyclane, Betahistine, Bradykinin, Brovincamine, Bufoniode,Buflomedil, Butalamine, Cetiedil, Ciclonicate, Cinepazide, Cinnarizine,Cyclandelate, Diisopropylamine Dichloracetate, Eledoisin, Fenoxidil,Flunarisine, Heronicate, Ifenprodil, Inositol Niacinate, Isoxsuprine,Kallidin, Kallikrein, Moxisylyte, Nafronyl, Nicametate, Nicergoline,Nicofuranose, Nicotinyl Alcohol, Nylidrin, Pentifylline, Pentoxifylline,Piribedil, Protaglandin E₁, Suloctidil and Xanthinal Niacinate.

138. Vasoprotectants such as Benzarone, Bioflavonoids, Chromocarb,Clobeoside, Diosmin, Dobesilate Calcium, Escin, Rolescutol,Leucocyanidin, Metescufylline, Quercetin, Rutin and Troxerutin.

139. Vitamins, vitamin sources, and vitamin extracts such as Vitamins A,B, C, D, E, and K and derivatives thereof, Calciferols, Glycyrrhiza andMecobalamin.

140. Vulnerary agents such as Acetylcysteine, Allantoin, Asiaticoside,Cadexomer Iodine, Chitin, Dextranomer and Oxaceprol.

141. Anticoagulants such as heparin.

142. Miscellaneous such as Erythropoietin (Hematinic), Filgrastim,Finasteride (Benign Prostate Hypertrophy), Interferon Beta 1—Alpha(Multiple Sclerosis) and Tretinonin (Urinary Incontinence).

The amount of active agent to be incorporated in the carrier compositionwill vary depending on the particular active agent, the desiredtherapeutic effect, and the time span for which the transdermal systemis to provide therapy. Normally, the amount of active agent in thetransdermal system can vary from about 0.1% to about 50%, and preferablyfrom about 0.1% to about 30% by weight based on the dry weight of thetotal adhesive matrix composition. For lower dose concentrationspermitted by this invention, such as with steroids and hormones, thepreferred amount is from about 0.1% to about 10%.

While not essential, it is preferred that the androgenic hormones beincorporated near, at or above saturation with respect to itsconcentration in the adhesive matrix composition.

The term “adhesive matrix composition” as used herein refers to anynon-aqueous adhesive material into which an active agent is solubilizedor homogeneously blended either without, or in combination or admixturewith, other ingredients useful for facilitating transdermal drugdelivery, such as crystallization inhibitors, solubility enhancers,permeation enhancers, solvents, co-solvents and other types ofadditives. An “adhesive” as used herein means any natural or syntheticmaterial that is capable of sticking to the site of topical application.The term “pressure-sensitive adhesive” as used herein refers to anadhesive which adheres instantaneously to most surfaces with theapplication of very slight pressure and remains permanently tacky. Anadhesive is a pressure-sensitive adhesive within the meaning of thatterm as used herein if it has the properties of an adhesivepressure-sensitive adhesive per se or functions as the same by admixturewith tackifiers, plasticizers, cross-linking agents or other additives.

Suitable adhesives include all of the non-toxic natural and syntheticpolymers known for or suitable for use in transdermal devices asadhesives including acrylic polymers, gums, silicone-based polymers(broadly referred to as “polysiloxanes”) and rubber-based adhesives suchas polyisobutylenes, polybutylenes, ethylene/vinyl acetate and vinylacetate based adhesives, styrene/butadiene adhesives, polyisoprenes,styrenes and styrene block copolymers and block amide copolymers.

Suitable polysiloxanes include silicone pressure-sensitive adhesiveswhich are based on two major components: a polymer, or gum, and atackifying resin. The polysiloxane adhesive is usually prepared bycross-linking the gum, typically a high molecular weightpolydiorganosiloxane, with the resin, to produce a three-dimensionalsilicate structure, via a condensation reaction in an appropriateorganic solvent. The ratio of resin to polymer is the most importantfactor which can be adjusted in order to modify the physical propertiesof polysiloxane adhesives. Sobieski, et al., “Silicone PressureSensitive Adhesives,” Handbook of Pressure-Sensitive AdhesiveTechnology, 2nd ed., pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold,New York (1989).

Further details and examples of silicone pressure-sensitive adhesiveswhich are useful in the practice of this invention are described in thefollowing U.S. Pat. Nos. 4,591,622; 4,584,355; 4,585,836; and 4,655,767.

Suitable silicone pressure-sensitive adhesives are commerciallyavailable and include the silicone adhesives sold under the trademarksBIO-PSA® by Dow Corning Corporation, Medical Products, Midland,Michigan.

In particularly preferred embodiments of the invention, the adhesivematrix composition comprises a pressure-sensitive adhesive, and morepreferably a blend of one or more pressure-sensitive acrylic polymersand polysiloxanes.

The term “acrylic polymer” is intended to be used interchangeably withthe terms acrylate polymer, polyacrylate and polyacrylic adhesivepolymers as used herein and as known in the art.

The acrylic polymers useful in practicing the invention are polymers ofone or more monomers of acrylic acids and other copolymerizablemonomers. The acrylic polymers also include copolymers of alkylacrylates and/or methacrylates and/or copolymerizable secondary monomersor monomers with functional groups. By varying the amount of each typeof monomer added, the cohesive properties of the resulting acrylicpolymer can be changed as is known in the art. In general, the acrylicpolymer is composed of at least 50% by weight of an acrylate or alkylacrylate monomer, from 0 to 20% of a functional monomer copolymerizablewith the acrylate, and from 0 to 40% of other monomers.

Acrylate monomers which can be used include acrylic acid, methacrylicacid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexylmethacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl acrylate, 2-ethylbutylmethacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexylacrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate,dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, and tridecylmethacrylate.

Functional monomers, copolymerizable with the above alkyl acrylates ormethacrylates, which can be used include acrylic acid, methacrylic acid,maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropylacrylate, acrylamide, dimethylacrylamide, acrylonitrile,dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate,tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate,methoxyethyl acrylate and methoxyethyl methacrylate and other monomershaving at least one unsaturated double bond which participates incopolymerization reaction in one molecule and a functional group on itsside chain such as a carboxyl group, a hydroxyl group, a sulfoxyl group,an amino group, an amino group and an alkoxyl, as well as a variety ofother monmeric units including alkylene, hydroxy-substituted alkylene,carboxylic acid-substituted alkylene, vynylalkanoate, vinylpyrrolidone,vinylpyridine, vinylpirazine, vinylpyrrole, vinylimidazole,vinylcaprolactam, vinyloxazole, vyinlacate, vinylpropionate andvinylmorpholine.

Further details and examples of acrylic adhesives which are suitable inthe practice of the invention are described in Satas, “AcrylicAdhesives,” Handbook of Pressure-Sensitive Adhesive Technology, 2^(nd)ed., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York(1989).

Suitable acrylic adhesives are commercially available and include thepolyacrylate adhesives sold under the trademarks DURO-TAK® by NationalStarch Company, Bridgewater, N.J.; GELVA® by Solutia, St. Louis, Mo.;HRJ by Schenectady International, Inc., Chicago, Ill.; and EUDRAGIT® byRoehm Pharma GmbH, Darmstadt, Federal Republic of Germany.

The amount of the adhesive to be used depends on the concentration ofactive agent used to achieve a therapeutic effect. Typically, theadhesive is in an amount of about 5% to about 90%, and preferably about10% to about 90%, and most preferably about 20% to about 75% by weightbased on the dry weight of the total adhesive matrix composition.

The adhesive matrix compositions of the present invention can alsocontain one or more solvents and/or co-solvents. Such solvents and/orco-solvents are those known in the art, and are non-toxic,pharmaceutically acceptable substances, preferably liquids, which do notsubstantially negatively affect the adhesive properties of thetransdermal system or the solubility of the active agents at theconcentrations used. The solvent and/or co-solvent can be for the activeagent or for the matrix materials, or both.

Suitable solvents include volatile liquids such as alcohols (e.g.,methyl, ethyl, isopropyl alcohols and methylene chloride); ketones(e.g., acetone); aromatic hydrocarbons such as benzene derivatives(e.g., xylenes and toluenes); lower molecular weight alkanes andcycloalkanes (e.g., hexanes, heptanes and cyclohexanes); and alkanoicacid esters (e.g., ethyl acetate, n-propyl acetate, isobutyl acetate,n-butyl acetate isobutyl isobutyrate, hexyl acetate, 2-ethylhexylacetate or butyl acetate); and combinations and mixtures thereof.

Suitable co-solvents include polyhydric alcohols, which include glycols,triols and polyols such as ethylene glycol, diethylene glycol, propyleneglycol, dipropylene glycol, trimethylene glycol, butylene glycol,polyethylene glycol, hexylene glycol, polyoxethylene, glycerin,trimethylpropane, sorbitol, polyvinylpyrrolidone, and the like.

Further suitable co-solvents include glycol ethers such as ethyleneglycol monoethyl ether, glycol esters, glycol ether esters such asethylene glycol monoethyl ether acetate and ethylene glycol diacetate;saturated and unsaturated fatty acids, mineral oil, silicone fluid,lecithin, retinol derivatives and the like, and ethers, esters andalcohols of fatty acids.

Although the exact amount of co-solvents that may be used in theadhesive matrix composition depends on the nature and amount of theother ingredients, such amount typically ranges from about 0.1% to about40%, and preferably from about 0.1% to about 30% by weight, and morepreferably from about 1% to about 20%, by weight based on the dry weightof the total adhesive matrix composition.

In certain embodiments of the invention, a permeation enhancer isincorporated into the adhesive matrix composition. The term “permeationenhancer” as used herein refers to substances used to increasepermeability and/or accelerate the delivery of an active agent throughthe skin or mucosa, and include monhydric alcohols such as ethyl,isopropyl, butyl and benzyl alcohols; or dihydric alcohols such asethylene glycol, diethylene glycol, or propylene glycol dipropyleneglycol and trimethylene glycol; or polyhydric alcohols such as glycerin,sorbitol and polyethylene glycol, which enhance drug solubility;polyethylene glycol ethers of aliphatic alcohols (such as cetyl, lauryl,oleyl and stearly) including polyoxyethylene (4) lauryl ether,polyoxyethylene (2) oleyl ether and polyoxyethylene (10) oleyl ethercommercially available under the trademark BRIJ® 30, 93 and 97 from ICIAmericas, Inc., and BRIJ® 35, 52, 56, 58, 72, 76, 78, 92, 96, 700 and721; vegetable, animal and fish fats and oils such as cotton seed, corn,safflower, olive and castor oils, squalene, and lanolin; fatty acidesters such as propyl oleate, decyl oleate, isopropyl palmitate, glycolpalmitate, glycol laurate, dodecyl myristate, isopropyl myristate andglycol stearate which enhance drug diffusibility; fatty acid alcoholssuch as oleyl alcohol and its derivatives; fatty acid amides such asoleamide and its derivatives; urea and urea derivatives such asallantoin which affect the ability of keratin to retain moisture; polarsolvents such as dimethyldecylphosphoxide, methyloctylsulfoxide,dimethyllaurylamide, dodecylpyrrolidone, isosorbitol, dimethylacetonide,dimethylsulfoxide, decylmethylsulfoxide and dimethylformamide whichaffect keratin permeability; salicylic acid which softens the keratin;amino acids which are penetration assistants; benzyl nicotinate which isa hair follicle opener; and higher molecular weight aliphaticsurfactants such as lauryl sulfate salts which change the surface stateof the skin and drugs administered and esters of sorbitol and sorbitolanhydride such as polysorbate 20 commercially available under thetrademark Tween® 20 from ICI Americas, Inc., as well as otherpolysorbates such as 21, 40,60, 61, 65, 80, 81, and 85. Other suitableenhancers include oleic and linoleic acids, triacetin, ascorbic acid,panthenol, butylated hydroxytoluene, tocopherol, tocopherol acetate,tocopheryl linoleate. If permeation enhancers are incorporated into theadhesive matrix composition, the amount typically ranges up to about30%, and preferably from about 0.1% to about 15%, by weight based on thedry weight of the total adhesive matrix composition.

In addition to permeation enhancers, there may also be incorporatedvarious pharmaceutically acceptable additives and excipients availableto those skilled in the art. These additives include tackifying agentssuch as aliphatic hydrocarbons, mixed aliphatic and aromatichydrocarbons, aromatic hydrocarbons, substituted aromatic hydrocarbons,hydrogenated esters, polyterpenes, silicone fluid, mineral oil andhydrogenated wood rosins. Additional additives include binders such aslecithin which “bind” the other ingredients, or rheological agents(thickeners) containing silicone such as fumed silica, reagent gradesand, precipitated silica, amorphous silica, colloidal silicon dioxide,fused silica, silica gel, quartz and particulate siliceous materialscommercially available as Syloid®, Cabosil®, Aerosil®, and Whitelite®,for purposes of enhancing the uniform consistency or continuous phase ofthe final composition. Other additives and excipients include diluents,stabilizers, fillers, clays, buffering agents, biocides, humectants,anti-irritants, antioxidants, preservatives, plasticizing agents,cross-linking agents, flavoring agents, colorants, pigments and thelike. Such substances can be present in any amount sufficient to impartthe desired properties to the carrier composition. Such additives orexcipients are typically used in amounts up to 25%, and preferably fromabout 0.1% to about 10%, by weight based on the dry weight of the totaladhesive matrix composition.

The adhesive matrix compositions according to the present invention canbe prepared by first mixing appropriate amounts of the polymeric plasticmaterial in volatile polar and/or non-polar organic liquids, such asthose previously described as suitable volatile solvents. Appropriateamounts of active agent(s) are then added to the mixture together withappropriate amounts of pressure-sensitive adhesive(s), solvent(s) and/orco-solvent(s), with or without enhancer(s), and thoroughly mixed. Themixture of the adhesive matrix composition is next formed into a film atambient temperature, preferably by coating or casting at a controlledspecified thickness onto a flexible sheet material, such as a releaseliner, followed by evaporation of the volatile solvents at elevatedtemperatures (e.g., by passing through an oven). The non-volatile orhigher boiling point solvents and/or co-solvents, such as the polyols,used in the carrier composition remain therein. The carrier compositionhas been coated or cast on the flexible sheet material, is thenlaminated to another flexible sheet material preferably a backing layer.Appropriate size and shape individual transdermal drug delivery systemsare cut and then packaged (e.g., pouched).

The order of steps, the amount of the ingredients, and the amount andtime of mixing may be important process variables which will depend onthe specific polymers, active agents, solvents and/or co-solvents,enhancers and additives and excipients used in the composition. Thesefactors can be adjusted by those skilled in the art, while keeping inmind the objects of achieving a solubilized active agent and providing auniform product that will also give desirable results.

Reference to FIG. 1 shows a matrix-type transdermal drug delivery system10 comprising a pressure-sensitive adhesive matrix composition layer 11,a release liner 12, and a backing layer 13. Removal of the release liner12 exposes the pressure-sensitive adhesive matrix composition fortopical application to the user.

Further details and examples of pressure-sensitive adhesives, enhancers,solvents, co-solvents, release liners, backing layers, and otheradditives, as well as transdermal systems generally, suitable inpracticing the invention are described in U.S. Pat. Nos. 5,474,787 and5,656,286, Ser. Nos. 09/161,312 and 60/115,927, all of which areassigned to Noven Pharmaceuticals, Inc. and incorporated herein byreference.

EXAMPLES

The above description and following specific examples are herebyillustrative of pharmaceutically acceptable matrix compositions andtransdermal drug delivery systems, and methods of making same, withinthe contemplation of the invention. The description and examples are inno way intended to be, or should be considered, limiting of the scope ofthe invention. And while efforts have been made to ensure accuracy withrespect to numbers used (such as amounts and temperatures), someexperimental error and deviation should be accounted for and/or allowed.

Example 1

An estradiol/norethindrone acetate pressure-sensitive adhesive matrixcomposition was prepared by combining 0.7 parts of estradiol and 3.0parts of norethindrone acetate along with 3.0 parts of ethyl cellulose(Ethocele® 10, Dow Chemical Corp., Midland, Mich.) in 30.0 parts ethylacetate, 15.0 parts of toluene and 10.0 parts isopropyl alcohol. Then12.2 parts of a polyacrylate adhesive (DURO-TAIE® 87-2510; NationalStarch Company, Bridgewater, N.J.) and 109.2 parts of a polysiloxaneadhesive (BIO-PSA® Q7-4603; Dow Corning Corp, Midland, Mich.) were addedand thoroughly mixed. Finally 9.0 parts of dipropylene glycol and 6.0parts oleyl alcohol were added and mixed thoroughly in an appropriatecontainer until the mixture was completely homogenous. The resultingcomposition had the ingredient concentrations on a dry weight percentbasis (i.e., after evaporation of volatile solvents) as shown below.

INGREDIENT DRUG WEIGHT % Polysiloxane Adhesive 66.3 (BIO-PSA ® 7-4603)Polyacrylate Adhesive 5.0 (DURO-TAK ® 87-2287) Ethyl Cellulose 10.0(Ethocel ® 10) Dipropylene Glycol 9.0 Olelyl Alcohol 6.0 Estradiol 0.7Norethindrone Acetate 3.0 100.0

Examples 2-9

In the following examples, the method of Example 1 was used with theappropriate amounts of starting materials to yield compositions havingthe following ingredient concentrations set forth in tabular form inTABLE II. Examples 2, 3, and 5 are presented as control formulations forcomparative purposes, but are not within the scope of the invention inas much as the resulting adhesive matrix compositions do not contain apolymeric plastic material.

TABLE II Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Ex. 9 Polysiloxane0.0 71.4 54.5 53.6 48.6 43.6 58.0 53.0 Adhesive (BIO-PSA ® 7-4502)Polysiloxane 66.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Adhesive (BIO-PSA ®7-4603) Polyacrylate 5.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Adhesive (DURO-TAK ® 87-2287) Polyacrylate 0.0 5.0 5.0 20.0 20.0 20.0 5.0 5.0 Adhesive(Gelva ® 788) Ethyl Cellulose 0.0 0.0 15.0 0.0 0.0 0.0 10.0 15.0(Ethocel ® 10) Ethyl Cellulose 0.0 0.0 0.0 0.0 5.0 10.0 0.0 0.0(Ethocel ® 20) Polyvinyl 0.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0pyrrolidone (KOLLI- DON ® 30) Polyvinyl 10.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0pyrrolidone (KOLLI- DON ® 90) Dipropylene 9.0 6.0 6.0 8.0 8.0 8.0 8.08.0 Glycol Oleyl Alcohol 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 Estradiol 0.71.6 3.5 2.4 2.4 2.4 3.0 3.0 Norethindrone 3.0 0.0 0.0 0.0 0.0 0.0 0.00.0 Acetate

What is claimed is:
 1. A transdermal delivery system for providing drugdelivery across skin in a mammal comprising: (a) a pharmaceuticallyacceptable pressure-sensitive adhesive matrix consisting essentially ofa blend of: (i) one or more adhesives selected from the group consistingof polyacrylates, polysiloxanes, polyisobutylene, polyisoprene,styrenes, styrene block copolymers and block amide copolymers in anamount from 20% to 75% by weight based on the dry weight of the totaladhesive matrix composition, (ii) an insoluble, non-adhesive ethylcellulose polymer having a solution viscosity in the range of 3 cps to40 cps, alone or in combination with an insoluble, non-adhesivecellulose ester in a total amount from 2.5% to 20% by weight based onthe dry weight of the total adhesive matrix composition, (iii) at leastone hydrophobic active agent, (iv) a hydrophilic crystallizationinhibitor selected from the group consisting of solublepolyvinylpyrrolidone, soluble cellulose and cellulose derivatives, andpolyethylene oxide in an amount from 5% to 15% by weight based on thedry weight of the total adhesive matrix composition, (v) a drugpermeation enhancer in an amount up to 15% by weight based on the dryweight of the total adhesive matrix composition, and (vi) a polyhydricalcohol solvent in an amount up to 20% by weight based on the dry weightof the total adhesive matrix composition; wherein the adhesive matrix iscapable of delivering the active agent at a substantially zero-orderkinetic rate for period of time in excess of 72 hours.
 2. Thetransdermal system according to claim 1, wherein the ethyl cellulosepolymer has a solution viscosity in the range of 3 cps to 22 cps.
 3. Thetransdermal system according to claim 1, wherein the ethyl. cellulosepolymer is combined with an insoluble, non-adhesive cellulose esterselected from the group consisting of cellulose acetate butyrate andcellulose acetate propionate.
 4. The transdermal system according toclaim 1, wherein the hydrophilic crystallization inhibitor is solublepolyvinylpyrrolidone.
 5. The transdermal system according to claim 1,wherein the one or more active agents are selected from the groupconsisting of steroidal and hormonal agents.
 6. The transdermal systemaccording to claim 5, wherein tie adhesives consist of 5%-40% by dryweight polyacrylate adhesive and 30%-90% by dry weight polysiloxaneadhesive, the polydric alcohol solvent is dipropylene glycol in anamount of 5%-10% by dry weight, the permeation enhancer is oleyl alcoholin an amount of 1%-10% by dry weight, the hydrophilic crystallizationinhibitor is soluble polyvinylpyrrolidone in an amount of 5%-15% by dryweight, and the hormonal agent consists of 17 β-estradiol in an amountof 0.1%-5% by dry weight alone or in combination with norethindroneacetate in an amount of 1%-7% by dry weight, said weights based on thedry weight of the total composition.